Glycosylated analogs of fusidic acid

ABSTRACT

Novel analogs of fusidic acid are described with one or more carbohydrate units attached. Certain glycosylated analogs of fusidic acid have enhanced solubility properties in diluents or excipient of choice as compared to unmodified fusidic acid. Certain glycosylated analogs may be employed as chemotherapeutic agents and particular analogs may be useful for fighting anti-microbial infections.

The present application is a Continuation of U.S. patent applicationSer. No. 80/623,335 filed Mar. 27, 1996, now U.S. Pat. No. 6,103,884.

FIELD OF THE INVENTION

The present invention relates to novel analogs of fusidic acid. Inparticular, the present invention relates to novel glycosylated analogsof fusidic acid. The present invention also relates to novelglycosylated analogs of fusidic acid that have different solubilityproperties than unmodified fusidic acid and that act as chemotherapeuticagents.

BACKGROUND OF THE INVENTION

The discovery of antibiotics was possibly the most important medicalbreakthrough of the twentieth century, making many previously lethalmicrobial infections easily treatable. However, the benefits ofantibiotic therapy have gradually given rise to a dangerous development,namely antibiotic-resistant microorganisms. Through the constant use,and often overuse, of antibiotics, mankind has begun the process ofselecting strains of bacteria which are resistant to many types ofantibiotics.

Physicians employ many strategies to deal with antibiotic resistance,including: aggressively searching for new antibiotics, prescribingexisting antibiotics in a more prudent and less frequent manner, andusing combinations of diverse antibiotics to treat infections. In orderto successfully employ the latter strategy, it is necessary to utilize acombination of antibiotics that have very different biochemical modes ofaction.

Fusidic acid is just such an antibiotic. Having a mode of actiondifferent than most antibiotics, fusidic acid is unlikely to havecross-resistance with other antibiotics against microorganisms.

A relatively new antibiotic, fusidic acid was discovered in 1962 byGodtfresden and coworkers [See Godtfresden et al., Lancet 1:928 (1962);and, Verbist, J. Antimicrob. Chemotherapy 25: Supp. B:1 (1990)]. It wasisolated from the fermentation broth of the fungus Fusidium coccineum.It is a steroid-like antibiotic belonging to the class of the fusidanes,chemically related to cephalosporin P₁ and to helvolic acid. Of thesefusidanes, however, only fusidic acid has been used clinically withsuccess.

Fusidic acid is most effective against Gram-positive bacteria. Inparticular, Staphylococcus aureus, S. epidermidis, Clostridium spp. andcorynebacteria are highly susceptible [See Verbist supra]. In addition,a few Gram-negative bacteria are susceptible, including Neisseria andBacteroides spp. However, most Gram negative organisms, includingGram-negative bacilli and fungi, all enterobacteria, Psuedomonas spp.,and other non-fermenters are resistant to treatment with fusidic acid.Fusidic acid exhibits moderate efficacy against streptococci,mycobacteria, and Nocardia spp.

Unquestionably, what gives fusidic acid its inherent usefulness in thetreatment of microorganisms resistant to other antibiotics is its uniquemode of action. Fusidic acid inhibits bacterial protein synthesis byinterference with the elongation factor G [See Tanaka et al., Biochem. &Biophys. Res. Commun. 30:278 (1968)]. Such a unique mode of actionexplains the absence of intrinsic cross-resistance between fusidic acidand any other antibiotics. For example, methicillin-resistantstaphylococci are usually susceptible to fusidic acid.

In addition to its usefulness against Gram-positive organisms andbacterial resistance to other antibiotics, there have been recentdiscoveries related to the use of fusidic acid, which may provide evenmore clinical benefits.

The use of fusidic acid in treating staphylococcal bone and jointinfections has been described [See Coombs, J. Antimicrob. Chemotherapy25: Supp. B:53 (1990)]. The usefulness of fusidic acid in the treatmentof acute osteomyelitis, septic arthritis, chronic osteomyelitis, andother infections encountered in orthopedic surgery merits continuedresearch into the use of fusidic acid for other orthopedic maladies.

Fusidic acid has also recently been shown to be highly effective intreating recurrent bronchopulmonary infections with Staphylococcusaureus suffered by patients having cystic fibrosis [See Jensen et al, J.Antimicrob. Chemotherapy 25: Supp. B:45 (1990)].

Perhaps the most exciting recent discovery is the possible use offusidic acid in the treatment of AIDS. As described by Barnes in aScience review[238:276 (1994)], fusidic acid was found by researchers inDenmark to have in vitro effectiveness against HIV as well as “strikingclinical improvement” in a 58-year-old Danish man stricken with AIDS.These discoveries have led to immediate efforts to determine whether ornot fusidic acid will be useful in the treatment of AIDS. So far, theclinical data have been mixed [See Youle et al, J. Acquired ImmuneDeficiency Syndromes 2:59 (1989); and, Hording et al, Scand. J. Infect.Disease 22:649 (1990)].

With numerous current uses as well as promising future applications,fusidic acid will remain an important pharmaceutical product for theforeseeable future. However, fusidic acid is practically insoluble inwater, and the method of choice for oral delivery of the drug is a filmcoated formulation of sodium fusidate (the sodium salt) ordiethanolamine fusidate (the diethanolamine salt). Both derivativespossess significant side-effects including rashes, gastro-intestinalupset, jaundice and other changes in liver function, venospasm,thrombophlebitis, and hemolysis. Clearly, there remains a need fordifferent means of formulation which allows for administration of theagent without inducing serious side-effects.

SUMMARY OF THE INVENTION

The present invention relates to novel analogs of fusidic acid. Inparticular, the present invention relates to novel glycosylated analogsof fusidic acid. The present invention also relates to novelglycosylated analogs of fusidic acid that have different solubilityproperties than unmodified fusidic acid and that act as chemotherapeuticagents.

A fusidic acid “derivative” or “analog” of the present invention has thefundamental structure of fusidic acid (see FIG. 1), namely a fusedfour-ring molecule possessing a steroid-like structure and analkyl/alkenyl side chain, with either one or more carbohydrate groupsattached. The analogs of the present invention have numerous uses.First, they may be successfully employed as standards for analyticaltechniques (e.g., HPLC) so that new derivatives can be easilyidentified. Second, the present invention contemplates in vivo use; inaccordance with the present invention, a member from the class of novelfusidic acid derivatives is to be delivered as a chemotherapeutic agent,and, in one possible application, to fight anti-microbial infections inthe body.

The present invention contemplates derivatives of fusidic acid that havedifferent solubility properties than fusidic acid. These differentsolubility properties are important because the glycosylated analogs offusidic acid can be delivered for in vivo use in an admixture withdiluent or excipient. It is not intended that the present invention belimited by the nature of the mixture. In one embodiment, the diluent orexcipient is propylene glycol. Propylene glycol is miscible in water anda number of organic solvents. Propylene glycol is often used as asubstitute for ethylene glycol or glycerol. It can be used as a solventfor oral and injectable drugs and is employed in ointments. [See Goodmanand Gilman, The Pharmacological Basis of Therapeutics 9477; and, U.S.P.N.F. 1247]. Dextrose dissolved in an aqueous solution is another diluentor excipient contemplated for this purpose. The aqueous solution usedwith dextrose can be a buffer or other aqueous solution. For thedifferent diluents or excipient, water or aqueous solutions can be usedto dilute the diluent or excipient.

In one embodiment, the present invention contemplates a fusidic acidderivative modified at the C-3 position by chemical, enzymatic, orbiological means, such that it contains a carbohydrate unit (See, e.g.,FIGS. 2, 3, 10, and 11). In another embodiment, the present inventioncontemplates a fusidic acid derivative modified at the C-24 and C-25positions by chemical, enzymatic, or biological means, such that thedouble bonds present at those positions in unmodified fusidic acid areboth reduced to single bonds. The later modifications can be incombination with other modifications, such as those outlined in thefirst embodiment. In another embodiment, the present inventioncontemplates a glycosylated analog of fusidic acid modified by chemical,enzymatic, or biological means such that (i) the double bonds at the C-2and C-3 positions of the saccharide unit bound directly to fusidic acidare both reduced to single bonds, and (ii) the double bonds at the C-24and C-25 positions of the aglycon are both reduced to single bonds.

In another embodiment, the present invention contemplates a fusidic acidderivative modified at the C-24 position by chemical, enzymatic, orbiological means, such that it has a hydroxyl group. In anotherembodiment, the present invention contemplates a fusidic acid derivativemodified at the C-24 position by chemical, enzymatic, or biologicalmeans so that the hydroxyl group introduced at the C-24 position has acarbohydrate unit. In another embodiment, the present inventioncontemplates a fusidic acid derivative modified at the C-24 and. C-3positions by chemical, enzymatic, or biological means such that bothpositions contain carbohydrate units.

In another embodiment, the present invention contemplates a fusidic acidderivative modified at the C-25 position by chemical, enzymatic, orbiological means, such that it has a hydroxyl group. In anotherembodiment, the present invention contemplates a fusidic acid derivativemodified at the C-25 position by chemical, enzymatic, or biologicalmeans so that the hydroxyl group introduced at the C-25 position has acarbohydrate unit. In another embodiment, the present inventioncontemplates a fusidic acid derivative modified at the C-25 and C-3positions by chemical, enzymatic, or biological means such that bothpositions contain carbohydrate units.

In another embodiment, the present invention contemplates a fusidic acidderivative modified at the C-11 position by chemical, enzymatic, orbiological means, such that it contains a carbonyl group as opposed tothe hydroxyl group present at that position in unmodified fusidic acid.In another embodiment, the present invention contemplates a fusidic acidderivative modified by chemical, enzymatic, or biological means, suchthat it contains one or more carbohydrate units having terminal hydroxylgroups which have been deprotected as opposed to having terminalhydroxyl groups which are protected. In yet another embodiment, thepresent invention contemplates a fusidic acid derivative modified bychemical, enzymatic, or biological means, such that the C-2 and C-3positions of any saccharide units bound directly to a hydroxyl group ofthe aglycon are both reduced to single bonds.

For all these embodiments, the present invention contemplates havingglycosylated analogs of fusidic acid or glycosylated analogs of modifiedforms of fusidic acid with either an α- or β-linkage between the oxygenatom of the hydroxyl group of the aglycon and the C-1 position of thesaccharide unit bound to fusidic acid. These two types of analogs areknown as the α-anomer and the β-anomer of the glycosylated analog.

The contemplated derivations may be prepared in a number of differentfashions, and the present invention contemplates many different possiblecombinations of these derivations giving rise to different fusidic acidanalogs.

The carbohydrate unit or units attached to fusidic acid in some of theaforementioned embodiments are exemplified but not limited to2,3-desoxy-2,3-dehydroglucose, 2,3-desoxy-2,3-dehydroglucose diacetate,glucoside, glucoside tetraacetate, mannoside, mannoside tetraacetate,galactoside, galactoside tetraacetate, alloside, alloside tetraacetate,guloside, guloside tetraacetate, idoside, idoside tetraacetate,taloside, taloside tetraacetate, rhamnoside, rhamnoside triacetate,maltoside, maltoside heptaacetate, 2,3-desoxy-2,3-dehydromaltoside,2,3-desoxy-2,3-dehydromaltoside pentaacetate, 2,3-desoxymaltoside,lactoside, lactoside tetraacetate, 2,3-desoxy-2,3-dehydrolactoside,2,3-desoxy-2,3-dehydrolactoside pentaacetate, 2,3-desoxylactoside,glucouronate, N-acetylglucosamine. In one embodiment, the presentinvention contemplates the use of carbohydrate unit or units havingfive-membered rings, known as furanoses. In one embodiment, the presentinvention contemplates the use of carbohydrate unit or units havingsix-membered rings, known as pyranoses. Combinations of furanoses andpyranoses are also contemplated.

In one embodiment, an analog of the present invention is a glycosylatedanalog of the fusidic acid molecule of FIG. 1 that has differentsolubility properties than fusidic acid itself.

In one embodiment, an analog of the present invention is a glycosylatedanalog wherein fusidic acid is glycosylated at the C-3 position. Anexample of an analog of the present invention is fusidic acid3-(4,6-di-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside)[FSA-G-1] (See FIG. 2). Another example of an analog of the presentinvention is fusidic acid3-(2,3-dideoxy-α-D-erythro-hex-2-enopyranoside) [FSA-G-2] (See FIG. 3).Another example of an analog of the present invention is fusidic acid3-[4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-6-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside][FSA-M-1] (See FIG. 10). Another example of an analog of the presentinvention is fusidic acid3-[4-O-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-6-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside][FSA-L-1] (See FIG. 11). Another example of an analog of the presentinvention is fusidic acid3-(4,6-bis-O-(chloroacetyl)-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside)[FSA-ClAc-G-1] (See FIG. 12). Another example of an analog of thepresent invention is fusidic acid3-[4-O-(2,3,4,6-tetra-O-(chloroacetyl)-α-D-glucopyranosyl)-6-O-(chloroacetyl)-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside][FSA-ClAc-M-1] (See FIG. 13). Another example of an analog of thepresent invention is fusidic acid3-[4-O-(2,3,4,6-tetra-O-(chloroacetyl)-β-D-galactopyranosyl)-6-O-(chloroacetyl)-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside][FSA-ClAc-L-1] (See FIG. 14). Another example of an analog of thepresent invention is fusidic acid3-[4-O-(α-D-glucopyranosyl)-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside][FSA-M-2] (See FIG. 15). Another example of an analog of the presentinvention is fusidic acid3-[4-O-(β-D-galactopyranosyl)-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside][FSA-L-2] (See FIG. 16).

In one embodiment, an analog of the present invention is a glycosylatedanalog wherein the secondary hydroxyl group at position C-11 is oxidizedto a carbonyl group. An example of an analog of the present invention is11-dehydrofusidic acid3-(4,6-di-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside)[FSA-G-3] (See FIG. 4). Another example of an analog of the presentinvention is 11-dehydrofusidic acid3-(2,3-dideoxy-α-D-erythro-hex-2-enopyranoside) [FSA-G-4] (See FIG. 5).

In one embodiment, an analog of the present invention is a glycosylatedanalog wherein fusidic acid is fully reduced at the C-24 and C-25 doublebond positions and the C-2 and C-3 positions of the saccharide unitdirectly bound to the aglycon. An example of an analog of the presentinvention is 24,25-dihydrofusidic acid3-(4,6-di-O-acetyl-2,3-dideoxy-α-D-erythro-hexanopyranoside) [FSA-G-5](See FIG. 6). Another example of an analog of the present invention is24,25-dihydrofusidic acid 3-(2,3-dideoxy-α-D-erythro-hexanopyranoside)[FSA-G-6] (See FIG. 7). Another example of an analog of the presentinvention is 11 -dehydro-24,25-dihydrofusidic acid3-(4,6-di-O-acetyl-2,3-dideoxy-α-D-ezythro-hexanopyranoside) [FSA-G-7](See FIG. 8). Another example of an analog of the present invention is11-dehydro-24,25-dihydrofusidic acid3-(2,3-dideoxy-α-D-erythro-hexanopyranoside) [FSA-G-8] (See FIG. 9).

In one embodiment, an analog of the present invention is a fusidic acidanalog that has protecting groups at positions C-3, C-11, and C-21. (SeeFIG. 17). In one embodiment, an analog of the present invention is afusidic acid analog that has protecting groups at positions C-3, C-11,and C-21 and an hydroxyl group at position C-24. (See FIG. 18). In oneembodiment, an analog of the present invention is a fusidic acid analogthat has a protecting group at position C-21 and an hydroxyl group atposition C-24. (See FIG. 19). In one embodiment, an analog of thepresent invention is a fusidic acid analog that has protecting groups atpositions C-3, C-11, and C-21 and at position C-24 a carbohydrate unithaving protecting groups. (See FIG. 20). In one embodiment, an analog ofthe present invention is a fusidic acid analog that has a carbohydrateunit at position C-24. (See FIG. 21). In one embodiment, an analog ofthe present invention is a fusidic acid analog that has a protectinggroup at position C-21 and at each of positions C-3 and C-24 acarbohydrate unit having protecting groups. (See FIG. 22). In oneembodiment, an analog of the present invention is a fusidic acid analogthat has a carbohydrate unit at each of positions C-3 ahd C-24. (SeeFIG. 23). In one embodiment, an analog of the present invention is afusidic acid analog that has protecting groups at positions C-3, C-11,and C-21 and an hydroxyl group at position C-25. (See FIG. 24). In oneembodiment, an analog of the present invention is a fusidic acid analogthat has a protecting group at position C-21 and an hydroxyl group atposition C-25. (See FIG. 25). In one embodiment, an analog of thepresent invention is a fusidic acid analog that has protecting groups atpositions C-3, C-11, and C-21 and at position C-25 a carbohydrate unithaving protecting groups. (See FIG. 26). In one embodiment, an analog ofthe present invention is a fusidic acid analog that has a carbohydrateunit at position C-25. (See FIG. 27). In one embodiment, an analog ofthe present invention is a fusidic acid analog that has a protectinggroup at position C-21 and at each of positions C-3 and C-25 acarbohydrate unit having protecting groups. (See FIG. 28). In oneembodiment, an analog of the present invention is a fusidic acid analogthat has a carbohydrate unit at each of positions C-3 and C-25. (SeeFIG. 29).

In one embodiment, an analog of the present invention is synthesized bya) providing in any order: i) unmodified fusidic acid, ii) aderivatizing reagent, and iii) a catalyst; b) reacting in any order: i)said unmodified fusidic acid, ii) said derivatizing reagent, and iii)said catalyst, under conditions such that a glycosylated analog of thefusidic acid molecule of FIG. 1 is formed having different solubilityproperties than unmodified fusidic acid itself.

In another embodiment, the derivatizing agents are those reagents whichprovide the substituents added to fusidic acid or a modified form offusidic acid. In one embodiment, the derivatizing agent is acarbohydrate glycal. In one embodiment, the carbohydrate glycal iseither glucose-derived glycal (glucal), lactose-derived glycal (lactal),or maltose-derived glycal (maltal). A catalyst, in general, is asubstance which increases the rate of a chemical reaction. In oneembodiment, the catalyst is BF₃etherate. In one embodiment, the catalystis a molecular diatomic halogen. In one embodiment, the moleculardiatomic halogen is molecular diatomic iodine.

In one embodiment, the carbohydrate glycal is a disaccharide glycal, forexample maltose glycal (maltal), and is synthesized by a) providing inany order: i) unmodified disaccharide, ii) a protecting reagent, iii) aderivatizing reagent, and iv) a reducing agent; b) reacting in anyorder: i) unmodified disaccharide and ii) a protecting reagent to form aprotected disaccharide; c) reacting in any order: i) the protecteddisaccharide of step (b) and ii) a derivatizing reagent to form aderivatized protected disaccharide; d) reacting in any order: i) thederivatized protected disaccharide of step (c) and ii) an reducing agentto form a disaccharide glycal. In one embodiment, the unmodifieddisaccharide is maltose. In one embodiment, the unmodified disaccharideis lactose. In one embodiment, the protecting reagent is an esterifyingreagent, for example acetic anhydride. In one embodiment, thederivatizing reagent is a halogenating reagent that introduces a halogenatom at the anomeric carbon atom of the carbohydrate, for examplehydrobromic acid. In one embodiment, the reducing agent is Zn/CuSO₄.

In one embodiment, the carbohydrate glycal is an activated carbohydrateglycal. Activated glycals are those glycals which have a sufficientreactivity to readily react with fusidic acid or a modified fusidic acidto form glycosylated analogs of fusidic acid or of modified fusidicacid. Activated glycals, by definition, are not the parent glycalthemselves. Activated glycals are synthesized by a) providing in anyorder: i) the glycal, ii) an activating reagent, and iii) a catalyst; b)reacting in any order: i) the glycal, ii) a protecting reagent, and iii)a catalyst, under conditions such that an activated carbohydrate glycalis formed. In one embodiment, the carbohydrate glycal is maltal.Activating reagents are those reagents that convert glycals intoactivated glycals. In one embodiment, the activating reagent is acarboxylic acid, for example, o-anisic acid. In one embodiment, thecatalyst is a molecular diatomic halogen. In one embodiment, themolecular diatomic halogen is molecular diatomic iodine.

In one embodiment, an analog of the present invention is synthesized bya) providing in any order: i) a modified fusidic acid, ii) aderivatizing reagent, and iii) a catalyst; b) reacting in any order: i)said modified fusidic acid, ii) said derivatizing reagent, and iii) saidcatalyst, under conditions such that a glycosylated analog of a modifiedform of the fusidic acid molecule of FIG. 1 is formed having differentsolubility properties than unmodified fusidic acid.

A modified form of fusidic acid is fusidic acid that has been modifiedby chemical, enzymatic, or biological means so that the modified fusidicacid may still form a glycosylated analog in the aforementionedreaction. In one embodiment, a modified form of fusidic acid is fusidicacid wherein the C-24 and C-25 positions having double bonds have beenreduced to single bonds. In another embodiment, the modified form offusidic acid is fusidic acid wherein the hydroxyl group at C-11 has beenoxidized to a carbonyl group. In another embodiment, the modified formof fusidic acid is fusidic acid wherein a hydroxyl group has beenintroduced at the C-24 position. For this modified form of fusidic acid,the carbon at C-24 may be either one of the two epimers, R or S. Thismodified form of fusidic acid may consist either of an approximatelyequal mixture of the two optical isomers at the C-24 position or anexcess of one optical isomer over the other. In another embodiment, themodified form of fusidic acid is fusidic acid wherein a hydroxyl grouphas been introduced at the C-25 position.

For each of these modified forms of fusidic acid, the molecule may haveother modifications termed “protecting groups” which prevent anyfunctional groups of the modified form of fusidic acid from interferingwith the glycosylation reaction. It may be the case that depending onwhether the modified form of fusidic acid has certain protecting groups,the modified form of fusidic acid may react with the derivatizingreagent to give a glycosylated analog of a modified form of the fusidicacid molecule having more than one carbohydrate unit bound directlythrough a hydroxyl group to the aglycon. In one embodiment, theprotecting group is an acyl. In one embodiment the acyl ismonochloroacetyl. In another embodiment, the protecting group is amethyl group.

In one embodiment, an analog of the present invention is synthesized bya) providing in any order: i) a glycosylated analog of fusidic acidhaving one or more protecting groups and ii) a deprotection agent; b)reacting in any order: i) said glycosylated analog of fusidic acidhaving one or more protecting groups and ii) the deprotecting reagent toform a glycosylated analog of fusidic acid having fewer protectinggroups.

Protecting groups are those groups which prevent undesirable reactionsinvolving unprotected functional groups. In one embodiment, protectinggroups protect the terminal hydroxyl groups of a carbohydrate unit. Inone embodiment, the protecting group is an acyl. In one embodiment, theacyl is acetate. In one embodiment, the acyl is monochloroacetyl. In oneembodiment, the acyl is methoxyacetyl. The prefix “per” indicates thatall hydroxyl groups in a particular carbohydrate unit are protected bythe designated functionality. For example, a “per-(ClOAc)-glycal” willhave monochloroacetyl groups bound to each hydroxyl group of thecarbohydrate unit. Deprotection reagents remove protecting groups. Forexample, in one embodiment, reaction of a glycosylated analog of fusidicacid with carbohydrate unit or units having protecting acyl groups witha deprotection reagent gives a glycosylated analog of fusidic acidhaving no protecting groups, i.e., the carbohydrate unit or units havedeprotected, free hydroxyl groups. This reaction is commonly known as ahydrolysis reaction. In one embodiment, the deprotecting reagent is achemical reagent which has properties of a nucleophile. In oneembodiment, the deprotecting reagent is Ba(OH)₂. In one embodiment, thedeprotecting reagent is NaHCO₃. In one embodiment, the deprotectingreagent is KHCO₃.

In one embodiment, an analog of the present invention is synthesized bya) providing in any order: i) a glycosylated analog of a modified formof fusidic acid having one or more protecting groups and ii) adeprotection agent; b) reacting in any order: i) a glycosylated analogof a modified form of fusidic acid having one or more protecting groupsand ii) the deprotecting reagent to form a glycosylated analog of amodified form of fusidic acid having fewer protecting groups.

As for the unmodified fusidic acid, protecting groups can protect theterminal hydroxyl groups of the carbohydrate unit or units. In oneembodiment, protecting groups protect functional groups of the aglycon.In one embodiment, the protecting group is an acyl. In one embodiment,the acyl is monochloroacetyl. In one embodiment, the protecting group ismethyl. In one embodiment, the deprotecting reagent is Ba(OH)₂. In oneembodiment, the deprotecting reagent is NaHCO₃. In one embodiment, thedeprotecting reagent is KHCO₃.

DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the structure of unmodified fusidic acid.

FIG. 2 shows the structure of a fusidic acid analog of the presentinvention: fusidic acid3-(4,6-di-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside)[FSA-G-1].

FIG. 3 shows the structure of a fusidic acid analog of the presentinvention: fusidic acid 3-(2,3-dideoxy-α-D-erythro-hex-2-enopyranoside)[FSA-G-2].

FIG. 4 shows the structure of a fusidic acid analog of the presentinvention: 11-dehydrofusidic acid3-(4,6-di-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside)[FSA-G-3].

FIG. 5 shows the structure of a fusidic acid analog of the presentinvention: 11-dehydrofusidic acid3-(2,3-dideoxy-α-D-erythro-hex-2-enopyranoside) [FSA-G-4].

FIG. 6 shows the structure of a fusidic acid analog of the presentinvention: 24,25-dihydrofusidic acid3-(4,6-di-O-acetyl-2,3-dideoxy-α-D-erythro-hexanopyranoside) [FSA-G-5].

FIG. 7 shows the structure of a fusidic acid analog of the presentinvention: 24,25-dihydrofusidic acid3-(2,3-dideoxy-α-D-erythro-hexanopyranoside) [FSA-G-6].

FIG. 8 shows the structure of a fusidic acid analog of the presentinvention: 11-dehydro-24,25-dihydrofusidic acid3-(4,6-di-O-acetyl-2,3-dideoxy-α-D-erythro-hexanopyranoside) [FSA-G-7].

FIG. 9 shows the structure of a fusidic acid analog of the presentinvention: 11-dehydro-24,25-dihydrofusidic acid3-(2,3-dideoxy-α-D-erythro-hexanopyranoside) [FSA-G-8].

FIG. 10 shows the structure of a fusidic acid analog of the presentinvention: fusidic acid3-[4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-6-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside][FSA-M-1].

FIG. 11 shows the structure of a fusidic acid analog of the presentinvention: fusidic acid3-[4-O-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-6-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside][FSA-L-1].

FIG. 12 shows the structure of a fusidic acid analog of the presentinvention: fusidic acid3-(4,6-bis-O-(chloroacetyl)-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside)[FSA-ClAc-G-1].

FIG. 13 shows the structure of a fusidic acid analog of the presentinvention: fusidic acid3-[4-O-(2,3,4,6-tetra-O-(chloroacetyl)-α-D-glucopyranosyl)-6-O-(chloroacetyl)-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside][FSA-ClAc-M-1].

FIG. 14 shows the structure of a fusidic acid analog of the presentinvention: fusidic acid3-[4-O-(2,3,4,6-tetra-O-(chloroacetyl)-β-D-galactopyranosyl)-6-O-(chloroacetyl)-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside][FSA-ClAc-L-1].

FIG. 15 shows the structure of a fusidic acid analog of the presentinvention: fusidic acid3-[4-O-(α-D-glucopyranosyl)-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside][FSA-M-2].

FIG. 16 shows the structure of a fusidic acid analog of the presentinvention: fusidic acid3-[4-O-(β-D-galactopyranosyl)-2,3-dideoxy-(α-D-erythro-hex-2-enopyranoside][FSA-L-2].

FIG. 17 shows the structure of a fusidic acid analog contemplated by thepresent invention that has protecting groups at positions C-3, C-11, andC-21.

FIG. 18 shows the structure of a fusidic acid analog contemplated by thepresent invention that has protecting groups at positions C-3, C-11, andC-21 and an hydroxyl group at position C-24.

FIG. 19 shows the structure of a fusidic acid analog contemplated by thepresent invention that has a protecting group at position C-21 and anhydroxyl group at position C-24.

FIG. 20 shows the structure of a fusidic acid analog contemplated by thepresent invention that has protecting groups at positions C-3, C-11, andC-21 and at position C-24 a carbohydrate unit having protecting groups.

FIG. 21 shows the structure of a fusidic acid analog contemplated by thepresent invention that has a carbohydrate unit at position C-24.

FIG. 22 shows the structure of a fusidic acid analog contemplated by thepresent invention that has a protecting group at position C-21 and ateach of positions C-3 and C-24 a carbohydrate unit having protectinggroups.

FIG. 23 shows the structure of a fusidic acid analog contemplated by thepresent invention that has a carbohydrate unit at each of positions C-3and C-24.

FIG. 24 shows the structure of a fusidic acid analog contemplated by thepresent invention that has protecting groups at positions C-3, C-11, andC-21 and an hydroxyl group at position C-25.

FIG. 25 shows the structure of a fusidic acid analog contemplated by thepresent invention that has a protecting group at position C-21 and anhydroxyl group at position C-25.

FIG. 26 shows the structure of a fusidic acid analog contemplated by thepresent invention that has protecting groups at positions C-3, C-11, andC-21 and at position C-25 a carbohydrate unit having protecting groups.

FIG. 27 shows the structure of a fusidic acid analog contemplated by thepresent invention that has a carbohydrate unit at position C-25.

FIG. 28 shows the structure of a fusidic acid analog contemplated by thepresent invention that has a protecting group at position C-21 and ateach of positions C-3 and C-25 a carbohydrate unit having protectinggroups.

FIG. 29 shows the structure of a fusidic acid analog contemplated by thepresent invention that has a carbohydrate unit at each of positions C-3and C-25.

FIG. 30 shows the structure of various glycals contemplated by thepresent invention that can be used as derivatizing agents.

DESCRIPTION OF THE INVENTION

The present invention relates to novel analogs of fusidic acid. Inparticular, the present invention relates to novel glycosylated analogsof fusidic acid that have different solubility properties thanunmodified fusidic acid itself. The present invention also relates toglycosylated analogs of fusidic acid that act as chemotherapeuticagents. The description of the present invention involves: (I)Properties of Unmodified Fusidic Acid and Properties of PreviouslyModified Fusidic Acid Derivatives (Prior Art); (II) Physical Propertiesof Fusidic Acid Analogs of the Present Invention; (III) Synthesis ofNovel Glycosylated Fusidic Acid Analogs; (IV) In Vivo Uses; (V)Methodology for Screening Glycosylated Analogs of Fusidic Acid AnalogsBased on Solubility Properties.

I. Fusidic Acid and Previously Described Derivatives

The present inventors are unaware of previous efforts directed atimproving the water solubility of fusidic acid by chemicalderivatization of the hydroxyl groups with hydrophilic groups. Chemicalmodifications of fusidic acid have been, as a rule, unsuccessful atgenerating fusidic analogs which have improved antibacterial orantiviral activity. One of the first and most comprehensive studies ofthe biological effects of chemical modification of the fusidic acidmolecule was undertaken by Godtfresden [See Godtfresden et al., J. Med.Chem. 9:15 (1966)]. Godtfresden and coworkers synthesized 51 derivativesof fusidic acid; none of these derivatives possessed improvedantibacterial activity.

II. Physical Properties of Fusidic Acid Analogs of the Present Invention

The fusidic acid analogs of the present invention will have differentsolubility properties in propylene glycol as compared to unmodifiedfusidic acid. The different solubility properties will most likely bedue to the novel carbohydrate groups attached to the relativelyhydrophobic fusidic acid ring system. The present invention contemplatesthat those glycosylated analogs of fusidic acid prepared withderivatizing agents that are monosaccharides, i.e., the glucose-derivedglycal (glucal), will have a greater solubility in solvents such aspropylene glycol as compared to unmodified flsidic acid. The presentinvention contemplates that those glycosylated analogs of fusidic acidprepared with derivatizing agents that have multiple saccharide unitssuch as disaccharides, i.e., the lactose-derived glycal (lactal) ormaltose-derived glycal (maltal), will have a diminished solubility insolvents such as propylene glycol as compared to unmodified fusidicacid.

In contrast, the present invention contemplates that those glycosylatedanalogs of fusidic acid prepared with derivatizing agents that havemultiple saccharide units such as disaccharides, i.e., thelactose-derived glycal (lactal) or maltose-derived glycal (maltal), willhave an increased solubility in solvents such as aqueous solutions ofdextrose as compared to unmodified fusidic acid.

III. Synthesis of Novel Glycosylated Fusidic Acid Analogs

Recent developments in the area of pharmaceutical science have centeredaround efforts to increase the bioavailability of known drugs bychemical derivatization [See Brown and Thomas, Aust. J. Pharm. Sci. 8:1(1979); Ji et al., J. Med. Chem. 33:2264 (1990); Stella et al., J. Med.Chem. 35:145 (1992); and, Kleeman et al., J. Med. Chem. 35:559 (1992)].One approach is to develop methods of glycosylating a variety ofmedicinally-important compounds with the objective of increasing aqueoussolubility while hopefully enhancing the pharmacological profile ofthese agents. Such a process could unlock the benefits of a broad arrayof biologically-active compounds with intrinsically modesthydrophilicity.

The chemistry of glycals is perfectly suited for addressing the aboveissues. Glycals, cyclic sugar derivatives containing a 1,2-double bond,are indispensable synthetic precursors in the field of carbohydratechemistry. Though this class of sugars was discovered by Fischer 80years ago [See Fischer and Zach, Preuss. Akad. Wiss. 16:3311 (1913)],there has recently been an immense volume of research using thesecompounds to synthesize complex polysaccharides and glycosylatedproducts.

One reaction in particular, discovered by Ferrier in 1969 [See Ferrier,J. Chem. Soc. C 570 (1969)] and in which glycals can be attached tovarious nucleophiles, allows synthetic chemists to attach carbohydratesto a variety of non-carbohydrate organic molecules. The resultingcompound is an O-glycoside in which a carbohydrate unit is attached toan oxygen atom of a typically hydrophobic aglycon (aglycon referring toa non-carbohydrate portion of a molecule). Although similarglycosylation reactions had been accomplished thermally using water,alcohols and phenols [See Helferich, Adv. Carbohydrate Chem. 7:209(1952); Ferrier, J. Chem Soc. 5443 (1964); and, Ferrier et al., J. ChemSoc. 3667 (1962)], the Ferrier reaction's use of boron trifluorideetherate greatly expanded the synthetic scope.

Despite its utility, the Ferrier reaction has been less successfullyapplied to the commercial glycosylation of medicinally useful compounds.Such reactions, preferably performed on a large scale, require the useof Lewis acid catalysts which are more efficient, less toxic, and lessharsh toward the aglycon. For example, since most of these strong Lewisacids spontaneously react with air and moisture, the use of these Lewisacids presents serious problems when handling them, particularly in thelarge-scale, industrial setting. For these reasons, the use of thenon-toxic, stable catalyst iodine, which is an extremely mild Lewis acidand yet according to the invention retains enough acidity to effectglycosylation, is the preferred reagent. [See U.S. Pat. No. 5,278,296,hereby incorporated by reference; pending U.S. patent application, Ser.No. 08/251,869, hereby incorporated by reference; and, pending U.S.patent application, Ser. No. 08/429,941, hereby incorporated byreference.]

In one preferred aspect, the invention concerns O-glycoside compoundsobtained by reacting an oxygen nucleophile compound and a glycosylatingagent selected from 3-acylated five- and six-membered glycals in thepresence of a catalytic amount of iodine (5-50 mol % with 20 mol % beingthe most representative) to provide a reaction mixture containing theglycosylated product.

The present invention contemplates the preparation of the necessaryglycals by the following procedure. First, the desired carbohydrate maybe obtained commercially in non-acetylated form and acetylated byreaction with acetic anhydride in acetic acid with a catalytic amount ofhydrobromic acid. The acetylated carbohydrate is thereafter converted toan acetylated carbohydrate halide (e.g., bromide, by reaction withhydrobromic acid in acetic acid). The acetylated carbohydrate halide isconverted to the acetylated glycal by reaction with Zn/CuSO₄. Theacetylated glycal can be converted into the more reactive o-anisoylderivatives by reaction with o-anisic acid (2-methoxybenzoic acid).

Glycals having substituted acetyl protecting groups can be prepared byfirst hydrolyzing the unsubstituted acetates of the glycals. Sodiummethoxide or ammonia in methanol can be used for this purpose.Subsequent reaction of the unprotected glycals with the appropriatereagents will give the desired protected glycals having substitutedacetyl groups. In the case of per monochloroacetyl glycals, reaction ofthe unprotected glycal with monochloroacetyl chloride and pyridine givesthe glycal protected by monochloroacetyl groups. In the case ofpermethdxyacetyl glycals, reaction of the deprotected glycal withdicyclohexylcarbodiimide, 4-(dimethylamino)pyridine, and methoxyaceticacid gives the glycal protected by methoxyacetyl groups. Other glycalshaving substituted acetyl protecting groups can be prepared in a similarfashion. These glycals, which are considered derivatizing agents, arethen reacted with fusidic acid or a modified form of fusidic acid.Alternatively, a commercially available acetylated carbohydrate may beused and thereby obviate the need for the initial reaction step.

For glycosylation, preferred glycals of the formulas A-F are illustratedin FIG. 30, where R is a lower alkyl group. R₁, R₂, and R₃ are the sameor different and represent an aliphatic acyl group, an aromatic acylgroup such as a benzoyl group, or, in the case of either R₁ or R₂, acarbohydrate unit.

Any of various suitable solvents can be used for the glycosylationreaction of which THF, acetone, diethyl ether, methylene chloride,chloroform, and benzene are preferred. The reaction temperature and timecan be varied, e.g., ranging from −78° C. to room temperature for about0.5 to 12 hours.

In another preferred aspect, the present invention contemplates partlyand completely deprotected glycosylated analogs of fusidic acid andglycosylated analogs of a modified fusidic acid. These deprotectedproducts are produced by hydrolysis of one or more acyl groups from theacylated glycosylated analogs by a deprotection agent. Deprotectingglycosylated analogs of fusidic acid or glycosylated analogs of modifiedfusidic acid must be done with care so as not to hydrolyze the acetateat C-16, a functionality that occurs naturally in fusidic acid and isessential for biological activity of fusidic acid. [See Godtfresden etal., J. Med. Chem. 9:15 (1966)].

In one embodiment, when the carbohydrate unit or units haveunsubstituted acetyl groups, then Ba(OH)₂ in methanol will hydrolyze theacetyl groups of the carbohydrate unit or units to give the free alcoholand carboxylic acid. When the carbohydrate unit or units havemonochloro-substituted acetyl groups, then NaHCO₃ or KHCO₃ in methanoland water will hydrolyze the acyl groups to give the unprotected, freealcohol. Under either of these conditions, the acetyl group at C-16 ofthe aglycon present in unmodified and underivatized fusidic acid willnot be hydrolyzed.

In one embodiment, the present invention contemplates introducing a newhydroxyl functionality into unmodified fusidic acid. Before oxidizingthe C-24, C-25 double bond of fusidic acid, the hydroxyl groups at C-3and C-11 and the C-21 carboxylic acid group must be protected withappropriate protecting groups. In one embodiment, acylation of thehydroxyl groups of fusidic acid gives monochloroacetates at C-3 andC-11. In one embodiment, methylation of the C-21 carboxylic acid offusidic acid with diazomethane gives its methyl ester derivative.

In one embodiment, the hydroxyl group can be added at C-24 throughhydroboration chemistry. The resulting product will have a chiral centerat C-24. If an achiral hydroboration reagent is employed, then theresulting chiral center at C-24 will consist of an epimeric mixture.Alternatively, the judicious choice of chiral hydroboration reagentsfollowed by oxidative cleavage of the resulting carbon-boron bond canprovide either the R or S epimer. In one embodiment, reaction of thehydroxyl group of the modified aglycon with a glycal will give aglycosylated analog of modified fusidic acid having a carbohydrate unitat position C-24. In one embodiment, subsequent hydrolysis of theprotecting groups introduced to the aglycon and the protecting groups ofthe carbohydrate unit will give a glycosylated analog of modifiedfusidic acid having no protecting groups.

In another embodiment, the hydroxyl group can be added at C-25 throughthe use of oxymercuration chemistry. In one embodiment, reaction of thehydroxyl group of the modified aglycon with a glycal will give aglycosylated analog of modified fusidic acid having a carbohydrate unitat position C-25. In one embodiment, subsequent hydrolysis of theprotecting groups introduced to the aglycon and the protecting groups ofthe carbohydrate unit will give a glycosylated analog of modifiedfusidic acid having no protecting groups.

In another embodiment, the protecting groups at C-3 and C-11 can behydrolyzed after introduction of the hydroxyl functionality at eitherC-24 or C-25 by treatment with a base. In one embodiment, the base isNaHCO₃. In one embodiment, the base is KHCO₃. In one embodiment,reaction of the modified fusidic acid having unprotected hydroxyl groupsat C-3 and C-24 with glycal will give a glycosylated analog of fusidicacid having a carbohydrate unit at each of positions C-3 and C-24. Inone embodiment, subsequent hydrolysis of the protecting group at C-21 ofthe aglycon and the protecting groups of the carbohydrate units willgive a glycosylated analog of modified fusidic acid having no protectinggroups. In another embodiment, reaction of the modified fusidic acidhaving unprotected hydroxyl groups at C-3 and C-25 with glycal will givea glycosylated analog of fusidic acid having a carbohydrate unit at eachof positions C-3 and C-25. In one embodiment, subsequent hydrolysis ofthe protecting group at C-21 of the aglycon and the protecting groups ofthe carbohydrate units will give a glycosylated analog of modifiedfusidic acid having no protecting groups.

IV. In Vivo Uses

The present invention contemplates using therapeutic compositions ofsoluble fusidic acid analogs. It is not intended that the presentinvention be limited by the particular nature of the therapeuticpreparation. For example, such compositions can be provided togetherwith physiologically tolerable liquid, gel or. solid carriers, diluents,adjuvants and excipient. In addition, fusidic acid analogs may be usedtogether with other chemotherapeutic agents, including unmodifiedfusidic acid.

With respect to the mode of administration, the fusidic acid analogs maybe employed for intravenous, intramuscular, intrathecal or topical(including topical ophthalmic) administration. Formulations for suchadministrations may comprise an effective amount of fusidic acid analogin sterile water or physiological saline.

On the other hand, formulations may contain such normally employedadditives as binders, fillers, carriers, preservatives, stabilizingagents, emulsifiers, buffers and 5 excipient as, for example,pharmaceutical grades of mannitol, lactose, starch, magnesium stearate,sodium saccharin, cellulose, magnesium carbonate, and the like.

These compositions typically contain 1%-95% of active ingredient,preferably 2%-70%.

The compositions can be prepared as injectables, either as liquidsolutions or suspensions; solid forms suitable for solution in, orsuspension in, liquid prior to injection may also be prepared.

The fusidic acid analogs of the present invention are often mixed withdiluents or excipient which are compatible and physiologicallytolerable. Suitable diluents and excipient are, for example, water,saline, ethylene glycol, dextrose, glycerol, or the like, andcombinations thereof. One preferred choice is propylene glycol. A secondpreferred choice is aqueous solutions of dextrose. In addition, ifdesired the compositions may contain minor amounts of auxiliarysubstances such as wetting or emulsifying agents, stabilizing or pHbuffering agents.

Options for optimal method of fusidic acid analog administrationinclude, but are not limited to: a 30-minute infusion every three weeks,a 30-minute infusion daily ×5 every three weeks, a 24-hour infusionevery three weeks, a 120-hour infusion every three weeks, and a 72-hourinfusion repeated every three weeks.

Likewise, dosage ranges for fusidic acid analog treatment include, butare not limited to: 1 to 50 mg/m²/day.

V. Methodology for Screening Glycosylated Analogs of Fusidic AcidAnalogs Based on Solubility Properties.

We claim glycosylated analogs of fusidic acid. These compounds may beprepared by either glycosylation of fusidic acid itself or a modifiedform of fusidic acid, and once glycosylated, the glycosylated analogsmay undergo a number of subsequent modifications. This section outlinesa procedure whereby a novel glycosylated analog of fusidic acid can bescreened for desired solubility properties. These desired solubilityproperties consist of an increased solubility of the glycosylated analogas compared to unmodified fusidic acid in different diluents orexcipient. The present invention contemplates the use of propyleneglycol as a diluent or excipient. The present invention contemplates theuse of aqueous solutions of dextrose as a diluent or excipient.

This screening procedure is proposed without intending to be limited tothe mechanism by which enhanced solubility is achieved in. differentdiluents or excipient. The present screening method also contemplatesthe use of aqueous solutions with the diluents or excipient. Theseaqueous solutions can be buffers, saline solution, or other aqueoussolutions having auxiliary substances.

Screening Procedure:

Mode I: Determine whether the aglycon unit of the glycosylated analog offusidic acid of interest possesses at least one hydroxyl functionalgroup which can be glycosylated with the glycal of interest.

Mode II: Determine whether the glycosylated analog of fusidic acid hasenhanced solubility properties in propylene glycol as compared tofusidic acid.

Mode III: Determine whether the glycosylated analog of fusidic acid hasenhanced solubility properties in aqueous solutions of dextrose ascompared to fusidic acid.

A new glycosylated analog of fusidic acid can be evaluated for thedesired solubility properties in propylene glycol according to theprocedure outlined in Table 1.

TABLE 1 Evaluation of Solubility Properties of Novel GlycosylatedAnalogs of Fusidic Acid Mode Result INTERPRETATION/NEXT STEP I +reactGlycosylation of aglycon unit of proposed glycosylated analog of fusidicacid is readily carried out. Perform glycosylation reaction (and anyother necessary modifications) and evaluate according to Mode II. −reactGlycosylation of aglycon unit of proposed glycosylated analog of fusidicacid is not readily carried out and should not be further evaluated. II+sol Glycosylated analog of fusidic acid has enhanced solubilityproperties in propylene glycol as compared to unmodified fusidic acid.The glycosylated analog of fusidic acid is useful. −sol Glycosylatedanalog of fusidic acid has similar or diminished solubility propertiesin propylene glycol as compared to unmodified fusidic acid. Evaluateaccording to Mode III. III +sol Glycosylated analog of fusidic acid hasenhanced solubility properties in aqueous solutions of dextrose ascompared to unmodified fusidic acid. The glycosylated analog of fusidicacid is useful. −sol Glycosylated analog of fusidic acid has similar ordiminished solubility properties in aqueous solutions as compared tounmodified fusidic acid. The glycosylated analog of fusidic acid is notuseful.

 Key: +react=glycosylation reaction possible; −react=glycosylationreaction not possible; +sol=enhanced solubility as compared tounmodified fusidic acid; −sol=similar or diminished solubility ascompared to unmodified fusidic acid.

EXPERIMENTAL

The following examples serve to illustrate certain preferred embodimentsand aspects of the present invention and are not to be construed aslimiting the scope thereof.

In the experimental disclosure which follows, the followingabbreviations apply: equiv (equivalents); M (molar); μM (micromolar); N(normal); mol (moles); mmol (millimoles); μmol (micromoles); nmol(nanomoles); g or gm (grams); mg (milligrams); μg (micrograms); L(liters); mL (milliliters); μL (microliters); cm (centimeters); mm(millimeters); μm (micrometers); nm (nanometers); ° C. (degreesCentigrade); TLC (thin layer chromatography); DMF(N,N-dimethylformamide); THF (tetrahydrofuran); Ac (—C═O)CH₃); ClAc(—C═O)CH₂Cl); Ph (a phenyl group, or —C₆H₅).

Compounds may be referred to by abbreviated names. For example,2,4,6-tri-O-acetyl-D-glucal may be identified as tri-O-acetyl-D-glucal,tri-O-acetyl-glucal, tri-acetyl-D-glucal, or tri-acetyl glucal. Theglycals derived from other sugars such as maltal and lactal will havesimilar variations on their nomenclature.

The Experimental has been broadly divided into three sections: I.Screening Experimental on the Basis of Solubility Properties; II.Synthesis of Reactants; III. Synthesis of Novel Analogs.

I. Screening Experimental on the Basis of Solubility Properties

The solubility properties of the glycosylated analogs of fusidic acid ofthe present invention will be measured in the diluent or excipient ofchoice by a spectrophotometric assay. An appropriate amount of theglycosylated analog of fusidic acid will be suspended in 1 mL of thediluent or excipient of choice in a 1.5 mL cryovial. The suspensionswill be mixed continuously on a Thermolyne vari-mix at room temperaturefor 24 hr. The suspensions then will be centrifuged at 14,000×g for 2minutes to separate the undissolved materials. The supernatant fluidswill be diluted appropriately with the diluent or excipient of choiceand the ultraviolet spectrums will be recorded on a Beckman 640 DUspectrophotometer. For comparison, a standard stock solution will beprepared for each glycosylated analog of fusidic acid in a solvent inwhich the compound is readily soluble. The ultraviolet spectrum will bemeasured. The solubility of each glycosylated analog of fusidic acid inthe solvent of choice will be calculated based on the following formula:

C_(unknown)=C_(standard)×(A_(unknown)×D_(dilution))/A_(standd)

where C_(unknown) is the concentration of the unknown solution to bedetermined; C_(standard) is the concentration of the standard workingsolution; A_(standard) is the absorbance at the appropriate wavelengthof the standard working solution; D_(dilution) is the appropriatedilution factor used so that the absorbance of the unknown workingsolution is within the dynamic range of the UV spectrophotometer(usually less than 1.25 absorbance units). The same assay will beconducted for fusidic acid in the excipient or diluent of choice, sothat a C_(unknown) for unmodified fusidic acid will be determined ineach diluent or excipient of choice.

The solubility properties of the glycosylated analogs of fusidic acidwill be compared to the solubility property of unmodified fusidic acidin the diluent or excipient of choice by comparing the C_(unknown)values that will have been determined from the assay. Those glycosylatedanalogs of fusidic acid that have a C_(unknown) that is gteater than 1.1times the C_(unknown) of unmodified fusidic acid in the diluent orexcipient of choice will be deemed to have enhanced solubilityproperties. Those glycosylated analogs of fusidic acid that have aC_(unknown) that is less than or equal to 1.1 times the C_(unknown) ofunmodified fusidic acid and greater than or equal to 0.9 times theC_(unknown) of unmodified fusidic acid in the diluent or excipient ofchoice will be deemed to have similar solubility properties. And thoseglycosylated analogs of fusidic acid that have a C_(unknown) that isless than 0.9 times the C_(unknown) of unmodified fusidic acid in thediluent or excipient of choice will be deemed to have diminishedsolubility properties.

II. Synthesis of Reactants EXAMPLE 1

This example describes the synthesis of tri-O-(chloroacetyl)-glucal.Bouhroum and Vottero have reported the prepation of this compound. [SeeBouuhroum and Vottero, Tetra. Letts. 31:7441 (1990)]. To a solution oftri-O-acetyl-glucal (18.0 g) in 150 mL of methanol was added 10 mL of25% sodium methoxide in methanol. The reaction mixture was stirred for 6h at room temperature, whereupon the solvent was removed and theresultant oil was dissolved by first adding 100 mL of methanol and then400 mL of THF. The solution was dried over anhydrous sodium sulfate,filtered, and concentrated to give 8.78 g (91%) of a yellowishsemi-solid. A portion of this product (3.26 g) was dissolved in 150 mLof THF and 15 g of pyridine, cooled to 0° C., and 8.32 g of chloroacetylchloride added. The solution was then allowed to warm to roomtemperature and was stirred overnight. The reaction mixture was thenpoured into 100 mL of ether and washed with 100 mL of water, 100 mL ofsaturated NaHCO₃, 100 mL of saturated aqueous CuSO₄, 50 mL of brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure.Silica gel chromatography (30% ethyl acetate in hexanes) of the crudeoil provided 6.01 g (64%) of tri-O-(chloroacetyl)-glucal as a yellowishoil. [α]_(D) ²⁰ −7.4® (c=1.00, CHCl₃); ¹H NMR (360 MHz, CDCl₃) δ 4.08(s, 2H), 4 .11 (s, 2H), 4.14 (s, 2H), 4.38 (m, 2H), 4.52 (dd, J=12.9,6.2 Hz, 1H), 4.90 (dd, J=6.2, 3.3 Hz, 1H), 5.32 (dd, J=8.0, 6.2 Hz, 1H),5.48 (m, 1H), 6.53 (dd, J=6.2, 1.1 Hz, 1H); ¹³C NMR (90 MHz, CDCl₃) δ40.53 (t), 40.64 (t), 40.75 (t), 62.57 (t), 68.49 (d), 68.98 (d), 73.29(d), 98.12 (d), 146.37 (d), 166.32 (s), 166.87 (s), 166.99 (s); IR(neat) 789 (w), 927 (w), 967 (w), 1026 (w), 1065 (w), 1104 (m), 1165(s), 1247 (mn), 1287 (m), 1315 (mn), 1411 (w), 1649 (w), 1763 (s), 2962(w) cm⁻¹.

EXAMPLE 2

This example describes the synthesis of tri-O-acetyl-glucal. While thecompound could be commercially obtained from Pfanstiehl LaboratoriesInc. (Wankeyan, Ill.), the procedure described below has the advantageof reduced cost as compared to the commercial source.

Glucose (1.00 g) was suspended in a solution of acetic acid (10 mL) andacetic anhydride (3.61 g, 7.0 equiv) and 1.00 g of 31% HBr/acetic acidwas added. The reaction mixture was stirred for 1 h, after which anadditional 9.00 g of a 31% .solution of HBr/acetic acid was added togive a total of 7.7 equiv of HBr, and the reaction mixture was stirredovernight. Sodium acetate was then added (2.70 g) to neutralize theexcess HBr, and the reaction mixture was added to a suspensioncontaining pulverized CuSO₄ 5H₂O (0.315 g), zinc (12.6 g), water (10mL), sodium acetate (9.450 g), and acetic acid (5 mL) and the resultantmixture was stirred vigorously for 1.5 h at room temperature. Thesolution was then filtered and the solid residue washed with ethylacetate (100 mL) and water (100 mL). The organic layer of the filtratewas washed with NaHCO₃ (100 mL) and brine (50 mL), dried over anhydroussodium sulfate, filtered, and the solvent removed under reduced pressureto provide tri-O-acetyl-glucal (1.35 g, 98%) as a colorless oil free ofimpurities as judged by ¹H NMR.

EXAMPLE 3

This example describes the synthesis ofdi-O-acetyl-O-((o-methoxy)benzoyl)-glucal. Tri-O-acetyl-glucal (1.00 g)was dissolved with o-anisic,acid (0.671 g, 1.2 equiv) and iodine (0.186g, 0.2 equiv) in 45 mL of THF and the solution was quickly cooled to−78° C. A 1 mm Hg vacuum line was then attached and the reaction mixtureallowed to warm slowly to −5° C. This reaction mixture was stirred for 2h under these conditions, replacing the lost THF solvent periodically.The reaction mixture was then poured onto 50 mL of ethyl acetate andwashed successively with saturated aqueous Na₂S₂O₃, saturated aqueousNaHCO₃, and brine. The organic layer was then dried over anhydroussodium sulfate, filtered, and the solvent removed under reducedpressure. The resultant crude oil was purified by silica gelchromatography (75% ethyl acetate in hexanes) to providedi-O-acetyl-O-((o-methoxy)benzoyl)-glucal (1.14 g, 85%) as a mixture of4 isomers. A 6:1 mixture of the α and β isomers could be separated forspectral analysis from a 1.4:1 mixture of the 3R and 3S isomers bysilica gel chromatography (20% ethyl acetate in hexanes). While thisexperimental procedure produces isomers, under the conditions in whichthe isomeric mixture is subsequently added to the aglycon (see Example27), a single intermediate will be formed resulting in a single finalstereochemical product.

α anomer: TLC R_(f) 0.56 (2:1 ethyl acetate:hexanes); [α]_(D) ²⁰+18.90°(c=1.02, CHCl₃) ¹H NMR (360 MHz, CDCl₃) δ 2.07 (s, 3H), 2.12 (s, 3H),3.91 (s, 3H), 4.26 (m, 3H), 5.43 (ddd, J=9.5, 3.2, 1.6 Hz, 1H), 6.00(1H) and 6.06 (1H) (ABq, J_(AB)=10.2 Hz, the 6.00 peaks are fer splitinto dd with J=2.8, 1.9 Hz, the 6.06 peaks are further split into ddwith J=0.8, 0.8 Hz), 6.56 (ddd, J=2.8, 0.9, 0.9 Hz, 1H), 6.99 (m, 2H),7.51 (ddd, J=8.1, 7.5, 1.8 Hz, 1H), 7.82 (dd, J=8.1, 1.8 Hz, 1H); ¹³CNMR (90 MHz, CDCl₃) δ 20.69 (q), 20.91 (q), 55.94 (q), 62.57 (t), 64.80(d), 69.17 (d), 88.33 (d), 112.11 (d), 119.31 (s), 120.09 (d), 126.18(d), 130.53 (d), 131.74 (d), 159.51 (s), 164.56 (s), 170.08 (s), 170.77(s); IR (KBr) 759 (w), 926 (m), 1044 (m), 1193 (w), 1236 (s), 1294 (w),1371 (w), 1438 (w), 1466 (w), 1492 (w), 1601 (w), 1743 (s) cm⁻¹.

3R and 3S isomers: TLC R_(f) 0.62 (2:1 ethyl acetate:hexanes); [α]_(D)²⁰+30.4° (c=1.01, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 2.03 (s, 3H, 3Sisomer), 2.09 (s, 3H, 3R isomer), 2.09 (s, 3H, 3R isomer), 2.10 (s, 3H,3S isomer), 3.90 (s, 3H), 4.22-4.53 (m, 3H), 5.04 (m, 1H), 5.24 (dd,J=10.1, 3.7 Hz, 1H, 3R isomer), 5.39 (dd, J=6.8, 5.8 Hz, 1H, 3S isomer),5.54 (dd, J=4.6, 3.8 Hz, 1H, 3S isomer), 5.71 (dd, J=6.8, 3.8 Hz, 1H, 3Risomer), 6.51 (d, J=6.2 Hz, 1H, 3S isomer), 6.58 (d, J=5.9 Hz, 1H, 3Risomer), 7.00 (m, 2H), 7.49 (m, 1H), 7.78 (m, 1H); ¹³C NMR (90 MHz,CDCl₃) δ 20.74 (q, 2C), 55.95 (q), 61.64 (t, 3S isomer), 62.04 (t, 3Risomer), 66.67 (d), 67.26 (d, 3R isomer), 67.34 (d, 3S isomer), 70.78(d, 3R isomer), 74.04 (d, 3S isomer), 97.77 (d, 3R isomer), 99.16 (d, 3Sisomer), 111.98 (d, 3S isomer), 112.15 (d, 3R isomer), 119.90 (s),120.16 (d), 131.47 (d, 3R isomer), 131.99 (d, 3S isomer), 133.73 (d, 3Risomer), 134.05 (d, 3S isomer), 145.56 (d, 3S isomer), 147.92 (d, 3Risomer), 159.30 (s), 165.36 (s), 169.54 (s), 170.69 (s); IR (KBr) 758(w), 1076 (m), 1128 (s), 1227 (w), 1295 (w), 1369 (w), 1438, 1468 (w),1492 (w), 1601 (w), 1647 (w), 1744 (s) cm⁻¹.

EXAMPLE 4

This example describes the synthesis of hexa-O-acetyl-maltal, which isnot commercially available. This procedure has the advantage of usingthe same solvent for the entire workup. Maltose monohydrate (1.00 g of amixture of 90% maltose, 10% glucose and maltatriose) was suspended in asolution of acetic acid (10 mL) and acetic anhydride (2.83 g, 10.0equiv) and 1.00 g of a 31% HBr/acetic acid solution was added. Thereaction mixture stirred for 1 h, after which 9.00 g more of a 31%HBr/acetic acid solution was added and allowed to stir overnight. Thereaction mixture was then poured into a suspension containing pulverizedCuSO₄ 5H₂O (0.182 g), zinc (7.290 g), water (10 mL), sodium acetate(5.470 g), and acetic acid (5 mL) and the resultant reaction mixture wasstirred vigorously for 1.5 h. The solution was then filtered and thesolid washed with ethyl acetate (100 mL) and water (100 mL). The organiclayer of the filtrate was then washed with NaHCO₃ (100 mL) and brine (50mL), dried over anhydrous sodium sulfate, filtered and the solventremoved under reduced pressure to provide a colorless oil which waspurified by silica gel chromatography (50% ethyl acetate in hexanes) togive hexa-O-acetyl-maltal (1.21 g, 86%) as a colorless solid andtri-O-acetyl-glucal (0.132 g, 88%) as a colorless oil. Regarding themaltose starting material, a more pure commercial sample would bepreferred, obviating the need for the aforementioned chromatographicseparation.

EXAMPLE 5

This example describes the synthesis ofpenta-O-acetyl-O-((o-methoxy)benzoyl)-maltal. Hexa-O-acetyl maltal (1.00g) was dissolved with o-anisic acid (0.326 g, 1.2 equiv) and iodine(0.090 g, 0.20 equiv) in 45 mL of THF and the solution was quicklycooled to −78° C. A 1 mm Hg vacuum line was then attached and thereaction mixture was allowed to warm slowly to −5° C. This reactionmixture was stirred for 3 h under these conditions, replacing the lostTHF solvent periodically. The reaction mixture was then poured onto 50mL of ethyl acetate and washed successively with saturated aqueousNa₂S₂O₃, saturated aqueous NaHCO₃, and brine. The organic layer was thendried over anhydrous sodium sulfate, filtered, and the solvent removedunder reduced pressure. The resultant crude oil was purified by silicagel chromatography (75% ethyl acetate in hexanes) to providepenta-O-acetyl-O-((o-methoxy)benzoyl)-maltal (1.103 g, 95%) as a mixtureof 4 isomers. An 8:1 mixture of the a and P anomers could be separatedfor spectral analysis from a mixture of the 3R and 3S isomers along witha small amount of starting hexa-O-acetyl-maltal by silica gelchromatography (20% ethyl acetate in hexanes).

α anomer: mp 59-60° C.; TLC R_(f) 0.48 (2:1 ethyl acetate:hexanes);[α]_(D) ²⁰+118.40 (c=1.03, CHCl₃); ¹H NMR (360 MHz, CDCl₃) δ 2.01 (s,3H), 2.03 (s, 3H), 2.04 (s, 3H), 2.09 (s, 3H), 2.11 (s, 3H), 3.37-4.52(m, 7H), 3.93 (s, 3H), 4.72-5.51 (m, 4H), 5.99 (1H) and 6.01 (1H) (ABq,J_(AB)=10.3), 6.53 (br s), 7.01 (m, 2H), 7.52 (dd, J=8.2, 7.5 Hz, 1H),7.84 (d, J=7.6 Hz, 1H); ¹³C NMR (90 MHz, CDCl₃) δ 20.54 (q, 5C), 55.98(q), 61.73 (t), 63.05 (t), 68.35 (d, 3C), 69.78 (d, 3C), 70.74 (d),88.21 (d) 94.44 (d), 112.19 (d), 119.53 (s), 120.10 (d), 126.24 (d),129.84 (d), 131.65 (d), 133.83 (d), 159.39 (s), 164.46 (s), 169.19 (s),169.71 (s), 169.82 (s), 170.16 (s, 2C).

EXAMPLE 6

This example describes the synthesis of hexa-O-acetyl-lactal. Lactose(1.00 g) was suspended in a solution of acetic acid (10 mL) and aceticanhydride (2.68 g, 9.0 equiv) and 1.00 g of a 31% HBr/acetic acidsolution was added. Although the solid lactose did not dissolve afterstirring for 1 h, an additional 9.00 g of a 31% HBr/acetic acid solutionwas added to the reaction mixture and the solution was stirred overnightat room temperature. The reaction mixture was then poured onto asuspension containing pulverized CuSO₄ 5H₂O (0.182 g), zinc (7.29 g),water (10 mL), sodium acetate (5.47 g), and acetic acid (5 mL), and theresultant reaction mixture was stirred vigorously for 1.5 h. Thesolution was then filtered and the solid residue washed with ethylacetate (100 mL) and water (100 mL). The organic layer of the filtratewas washed with NaHCO₃ (100 mL) and brine (50 mL), dried over anhydroussodium sulfate, filtered and the solvent removed under reduced pressureto provide a colorless solid which was purified by silica gelchromatography (50% ethyl acetate/hexanes) to give hexa-O-acetyl-lactal(1.01 g, 61%).

EXAMPLE 7

This example describes the synthesis ofpenta-O-acetyl-O-((o-methoxy)benzoyl)-lactal. Hexa-O-acetyl-lactal (1.00g) was dissolved with o-anisic acid (0.326 g, 1.2 equiv) and iodine(0.090 g, 0.20 equiv) in 45 mL of THF and quickly cooled to −78° C. A 1mm Hg vacuum line was then attached and the reaction mixture allowed towarm slowly to −5° C. This reaction mixture was stirred for 3 h underthese conditions, replacing the lost THF solvent periodically. Thereaction mixture was then poured onto 50 mL ethyl acetate and washedsuccessively with saturated aqueous Na₂S₂O₃, saturated aqueous NaHCO₃,and brine. The organic layer was dried over anhydrous sodium sulfate,filtered, and the solvent removed under reduced pressure. The resultantcrude oil was purified by silica gel chromatography (75% ethyl acetatein hexanes) to provide penta-O-acetyl-O-((o-methoxy)benzoyl)-lactal(1.00 g, 86%) as an inseparable mixture of 4 isomers.

EXAMPLE 8

This example describes the synthesis of hexa-O-(chloroacetyl)-maltal.Hexa-O-acetyl-maltal (4.50 g) was dissolved in 70 mL of methanol and0.400 g of sodium methoxide was added. The solution was stirred at roomtemperature overnight, whereupon the solvent was removed under reducedpressure. Silica gel chromatography (25% methanol in ethyl acetate)provided 2.20 g of a syrup which was immediately dissolved in a mixtureof 25 mL of DMF, 25 mL of THF and 5.64 g of pyridine. The reactionmixture was cooled to 0°, 8.06 g of chloroacetyl chloride was added, andthe reaction mixture was allowed to warm to room temperature and wasstirred for 3 hours. The mixture was poured onto 350 mL of CH₂Cl₂, theresultant mixture was washed successively with 500 mL of water (2×), 200mL of saturated aqueous CuSO₄, 200 mL of saturated aqueous NaHCO₃, and200 mL of brine. The organic layer was dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. The crudesolid was purified by silica gel chromatography (30% ethyl acetate inhexanes) to provide 3.22 g (52% from hexa-O-acetyl-maltal) ofhexa-O-(chloroacetyl)-maltal as a light yellow solid.

[α]_(D) ²⁰+43.40 (c=1.05, CHCl₃); ¹H NMR (360 MHz, CDCl₃) δ 4.00 (s,2H), 4.00-4.15 (m, 2H), 4.05 (s, 2H), 4.07 (s, 4H), 4.15 (s, 4H),4.27-4.53 (m, 5H), 4.91 (dd, J=5.4, 4.4 Hz, 1H), 4.95 (dd, J=10.1, 3.9Hz, 1H), 5.14 (dd, J=10.1, 9.7 Hz, 1H), 5.24 (br s, 1H), 5.50 (d, J=4.3Hz, 1H), 5.53 (dd, J=10.8, 9.7 Hz, 1H), 6.52 (d, J=Hz, 1H); ¹³C NMR (90MHz, CDCl₃) δ 40.25 (t, 2C), 40.29 (t), 40.58 (t), 40.63 (t), 40.71 (t),62.86 (t), 63.06 (t), 68.01 (d), 69.20 (d), 69.43 (d), 70.85 (d), 71.42(d), 73.09 (d), 73.45 (d), 95.77 (d), 97.40 (d), 146.23 (d), 166.40 (s),166.68 (s), 166.73 (s), 166.48 (s), 166.98 (s, 2C); IR (KBr) 569 (w),703 (w), 763 (w), 792 (m), 927 (m), 959 (m), 1009 (m), 1046 (s), 1167(s), 1249 (m), 1287 (m), 1313 (m), 1410 (m), 1649 (w), 1761 (s), 2961(w) cm⁻¹.

EXAMPLE 9

This example describes the synthesis of hexa-O-(chloroacetyl)-lactal.Hexa-O-acetyl-lactal (4.00 g) was dissolved in 70 mL of methanol and0.400 g of sodium methoxide was added. The solution was stirred at roomtemperature for 2 days, during which time a white solid appeared. Thereaction mixture was cooled to 0°, filtered through a sintered glassfunnel, and washed with 5 mL ice-cold methanol The white solid (1.49 g,67%) was dried under reduced pressure and 0.900 g was dissolved in 2.00g of pyridine and 25 mL of DMF. The reaction mixture was cooled to 0°,whereupon 2.40 g of chloroacetyl chloride was added. The reactionmixture was allowed to warm to room temperature and was stirredovernight. The mixture was poured onto 100 mL of CH₂Cl₂, and theresultant mixture was washed successively with 100 mL of water (2×), 50mL of saturated aqueous CuSO₄, 50 mL of saturated aqueous NaHCO₃, and 50mL of brine. The organic layer was dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. The crude solid waspurified by silica gel chromatography (30% ethyl acetate in hexanes) toprovide 1.41 g (42% from hexa-O-acetyl-lactal)hexa-O-(chloroacetyl)-lactal as a light yellow solid.

mp 56-58° C.; [α]_(D) ²⁰ −12.70 (c=1.03, CHCl₃); ¹H NMR (360. MHz,CDCl₃) δ 3.99 (s, 2H), 4.04-4.20 (m, 1H), 4.08 (s, 2H), 4.11 (s, 2H),4.12 (s, 2H), 4.14 (s, 2H), 4.20 (s, 2H), 4.21-4.38 (m, 5H), 4.54 (dd,J=12.0, 3.2 Hz, 1H), 4.83 (d, J=7.6 Hz, 1H), 4.87 (dd, J=6.2, 3.6 Hz,1H), 5.19 (1H) and 5.25 (1H) (ABq, J_(AB)=10.5 Hz; the 5.19 and 5.25 arefurther split into d with J=3.2 Hz and 7.6 Hz, respectively), 5.47 (d,J=2.4 Hz, 1H), 5.52 (dd, J=4.3,4.1 Hz, 1H), 6.47 (d, J=6.2 Hz, 1H); ¹³CNMR (90 MHz, CDCl₃) δ 40.23 (t), 40.39 (t, 2C), 40.50 (t), 40.67 (t),40.87 (t), 62.33 (t), 62.81 (t), 68.51 (d), 69.83 (d), 70.07 (d), 70.46(d), 71.88 (d), 73.81 (d), 73.90 (d), 97.90 (d), 100.17 (d), 146.22 (d),165.96 (s), 166.50 (s), 166.56 (s), 166.84 (s), 167.01 (s), 167.20 (s);IR (KBr) 791 (w), 926 (w), 958 (w), 1037 (m), 1075 (m), 1165 (s), 1247(m), 1286 (m), 1315 (m), 1410 (m), 1651 (w), 1759 (s), 2960 (w) cm⁻¹.

EXAMPLE 10

This example describes the synthesis of tri-O-(methoxyacetyl)-glucal.Tri-O-acetyl-glucal (13.5 g) was dissolved in 100 mL of methanol andammonia was bubbled through the solution until 5.60 g dissolved. Thereaction mixture was stirred overnight whereupon the solvent was removedunder reduced pressure. The resultant oil was then triturated with 100mL of a 5:1 CHCl₃:hexanes solution. The solid thus obtained wasdissolved in 100 ml of THF and the solution was treated withdicyclohexylcarbodiimide (35.00 g), 4-(dimethylamino)pyridine (0.500 g),and methoxyacetic acid (15.0 g). The reaction mixture was stirredovernight and filtered. After dilution with 300 mL of ether, thesolution was washed first with 300 mL of saturated aqueous NaHCO₃ andthen with 300 mL of brine, dried over anhydrous sodium sulfate,filtered, and the solvent removed under reduced pressure. Silica gelchromatography (30% ethyl acetate in hexanes) of the crude productprovided 6.33 g (35%) of tri-O-(methoxyacetyl)-glucal as a colorlessoil.

[α]_(D) ²⁰ −1.1° (c=1.20, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 3.43 (s,3H), 3.43 (s, 3H), 3.45 (s, 3H), 4.02 (s, 2H), 4.06 (s, 2H), 4.09 (s,2H); 4.26-4.33 (m, 2H), 4.53 (dd, J=6.6, 5.6 Hz, 1H), 4.86 (dd, J=6.1,3.1 Hz, 1H), 5.33 (dd, J=8.3, 6.1 Hz, 1H), 5.52 (m, 1H), 6.49 (dd,J=6.1, 1.3 Hz, 1H); ¹³C NMR (76 MHz, CDCl₃) δ 59.33 (q, 3C), 61.33 (t),67.48 (d), 68.12 (d), 69.45 (t, 2C), 69.61 (t), 73.73 (d), 98.71 (d),145.95 (d), 168.99 (s), 169.65 (s), 169.71 (s); IR (neat) 720, 754, 825,933, 969, 1024, 1065, 1128 (s), 1190 (s), 1246 (m), 1407 (w), 1422 (w),1452 (m), 1650 (m), 1760 (s), 2829 (m), 2936 (m) cm⁻¹.

EXAMPLE 11

This example describes the synthesis of hexa-O-(methoxyacetyl)-maltal.Hexa-O-acetyl-maltal (20.0 g) was dissolved in 100 mL of methanol andammonia was bubbled through the solution until 9.80 g dissolved. Thereaction mixture was stirred overnight whereupon the solvent was removedunder reduced pressure. The resultant oil was triturated three timeswith 80 mL of CHCl₃. The solid thus obtained was dissolved in 200 mL ofTHF and the solution was treated with dicyclohexylcarbodiimide (45.0 g),4-(dimethylamino)pyridine (0.500 g), and methoxyacetic acid (20.0 g).The reaction mixture was stirred overnight, filtered, and diluted with300 mL of ether. The resulting mixture was washed first with 300 mL ofsaturated aqueous NaHCO₃ and then with 300 mL of brine, dried overanhydrous sodium sulfate, filtered, and the solvent removed underreduced pressure. Silica gel chromatography (75% ethyl acetate inhexanes) of the crude product provided 7.22 g ofhexa-O-(methoxyacetyl)-maltal (30%) as a colorless oil.

[α]_(D) ²⁰+50.70 (c=1.08, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 3.38 (s,3H), 3.39 (s, 3H), 3.41 (s, 3H), 3.43 (s, 3H), 3.44 (s, 3H), 3.45 (s,3H), 3.94 (s), 2H), 3.99 (s, 4H), 4.01 (d, J=2.2 Hz, 2H), 4.09 (s, 4H),3.97-4.14 (m, 2H), 4.23 (1H) and 4.31 (1H) (ABq, J_(AB)=12.5 Hz, the4.23 and the 4.31 peaks are further split into d, J=2.2 and 4.0 Hz,respectively), 4.36-4.46 (m, 3H), 4.88 (dd, J=6.1, 3.3 Hz, 1H), 4.95(dd, J=10.2, 4.0 Hz, 1H), 5.14 (dd, J=10.2, 9.5 Hz, 1H), 5.21 (dd,J=4.1, 4.1 Hz), 5.45 (dd, J=4.1 Hz, 1H), 5.48 (dd, J=9.5, 9.5 Hz, 1H),6.46 (dd, J=6.2, 1.1 Hz); ¹³C NMR (90 MHz, CDCl₃) δ 59.34 (q, 2C), 59.42(q, 4C), 61.59 (t), 61.71 (t), 68.07 (d), 68.22 (d), 68.43 (d), 69.27(t, 2C), 69.31 (t), 69.43 (t), 69.57 (t), 69.72 (t), 70.11 (d), 70.36(d), 72.95 (d), 73.77 (d), 95.95 (d), 97.93 (d), 145.93 (d), 169.19 (s),169.51 (s), 169.67 (s), 169.77 (s), 169.89 (s), 169.96 (s); IR (neat)722 (w), 932 (m), 1045 (s), 1125 (s), 1183 (s), 1246 (s), 1375 (m), 1421(m), 1452 (m), 1650 (m), 1762 (s), 2829 (m), 1935 (m), 2829 (m), 2935(m) cm⁻¹.

EXAMPLE 12

This example describes the synthesis of fusidic acid [3α, 11α,16β-Trihydroxy-29-nor-8α,9β, 13β, 14β-dammara-17(20),24-dien-21-oic acid16-acetate]. Four Fusidin 1-gram tablets (obtained from Leo LaboratoriesLimited, Dublin, Ireland), each containing 250 mg of sodium fusidate(1.96 mmol), were crushedin a mortar. The white powder was dissolved inwater (100 mL) and the solution was acidified with 10% aqueoushydrochloric acid to make the pH of the solution 2-3. The aqueous layerwas extracted with chloroform (3×100 mL). The combined organic layerswere dried over anhydrous magnesium sulfate and the solvent was removedunder reduced pressure, providing fusidic acid as a white powder (940mg, 98% recovery). Spectroscopic data were identical with thosereported. [See Riisom et al., Tetra. Letts. 2247 (1974)].

II. Synthesis of Novel Analogs

EXAMPLE 13

This example describes the synthesis of fusidic acid3-(4,6-di-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside)[FSA-G-1]. To a solution of fusidic acid (1.03 g, 1.99 mmol) andtri-O-acetyl-glucal (0.701 g, 2.57 mmol) in dry tetrahydrofuran (30 mL)was added iodine (139 mg, 20 mol %) at room temperature under nitrogenatmosphere. The mixture was stirred for 2.5 hr, whereupon the reactionmixture was diluted with diethyl ether (45 mL). The resulting mixturewas washed with 0.1 M aqueous Na₂S₂O₃ (30 mL) and 10% aqueous NaHCO₃ (30mL). The organic layer was dried over anhydrous magnesium sulfate andthe solvent was removed under reduced pressure. The resulting oilyresidue was purified by silica gel flash chromatography usingdichloromethane/ethyl acetate/methanol (5/1/0 to 3/3/1) as the eluent,providing FSA-G-1 (>20:1 α/β-anomers) as a white powder (1.04 g, 72%):mp 111-112°; TLC R_(f) 0.60 (9/1 dichloromethane/methanol); [α]_(D)²¹−1.5° (c=0.2, CHCl₃); ¹H NMR of the α-anomer (360 MHz, CDCl₃) δ 0.87(d, 3H, J=6.6 Hz, 30-CH₃), 0.91 (s, 3H, 19-CH₃), 0.97 (s, 3H, 18-CH₃),1.36 (s, 3H, 32-CH₃), 159 (s, 3H, 26-CH₃), 1.68 (s, 3H, 27-CH₃), 1.96(s, 3H, 16-OAc), 2.09 (s, 3H, 16-OAc), 2.11 (s, 3H, 16-OAc), 3.05 (brd,1H, J=10.8 Hz, 13-H), 3.66 (m, 1H, 3-H), 4.16 (m, 3H, 4.16 (m, 3H, 5′-,6′-, 6″-H), 4.30-4.36 (m, 1H, 11-H), 5.04 (s, 1H, 1′-H), 5.10 (dd, 1H,J=7.1, 7.1 Hz, 24-H), 5.28 (d, 1H, J=9.6 Hz, 4′-H), 5.82 (br d, 1H,J=11.1, Hz, 2′-H), 5.89 (d, 1H, J=8.2 Hz, 16-H); ¹³C NMR of the α-anomer(90.6 MHz, CDCl₃) δ 15.74, 717.66, 17.88, 20.51, 20.73, 20.94, 22.71,24.08, 25.61, 28.28, 28.63, 28.85, 31.09, 32.28, 35.42, 36.27, 36.76,36.86, 38.85, 39.26, 44.22, 48.60, 49.07, 63.23, 65.50, 66.67, 67.66,68.17, 74.30, 81.07, 96.56, 122.89, 128.13, 128.21, 129.45, 132.53,151.04, 170.28, 170.47, 170.80, 174.56; IR (KBr) 3539-3507 (br), 2954(s), 1744 (s), 1698 (s), 1374 (s), 1238 (s), 1037 (s), 755 (s) cm⁻¹.Anal. Calcd for C₄₁H₆₀O₁₁1/2 CHCl₃: C, 63.21; H, 7.73. Found: C, 63.17;H, 7.49.

EXAMPLE 14

This example describes the synthesis of fusidic acid3-(2,3-dideoxy-α-D-erythro-hex-2-enopyranoside) [FSA-G-2]. To a solutionof FSA-G-1 (364 mg, 0.57 mmol) in methanol (10 mL) was added 0.1 Maqueous Ba(OH)₂ (9 mL) at room temperature. The mixture was stirred for3 hr, whereupon the solution was extracted with 4/1 chloroform/1-butanol(3×50 mL). The combined organic layers were dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The cruderesidue thus obtained was purified by silica gel flash chromatographyusing a chloroform to ethyl acetate gradient as the eluent, providingFSA-G-2 (>100:1 α/β-anomers) as a white powder (165 mg, 45%): mp129-131°; TLC R_(f) 0.20 (9/1 dichloromethane/methanol); [α]_(D)²¹−29.20 (c=2.01,CHCl₃); ¹H NMR (360 MHz, CDCl₃)δ 0.87 (d, 3H, J=6.0 Hz,30-CH₃), 0.89 (s, 3H, 19-CH₃), 0.97 (s, 3H 18-CH₃), 1.33 (s, 3H,32-CH₃), 1.59 (s, 3H, 26-CH₃), 1.67 (s, 3H, 27-CH₃), 1.97 (s, 3H,16-OAc), 3.01 (br s, 1H, 13-H), 3.56-3.62 (br s, 1H, 3-H), 3.78-3.88 (m,3H, 5′-, 6′-, 6″-H), 4.09 (br s, 1H, 4′-H), 4.31 (br s, 1H, 11-H), 4.97(s, 1H, 1′-H), 4.97 (br s 1H, 24-H), 5.73 and 5.93(AB_(q),2H,J_(AB)=10.0 Hz, 2′-H and 3′-H, respectively), 5.85 (br s,1H,16-H); ¹³C-NMR (90.6 MHz, CDCl₃)δ 15.74, 17.70 (2×C), 20.57, 20.79,23.20, 23.69, 25.64, 28.48, 28.79, 30.74, 31.84, 35.40, 36.49 (2×C),36.60, 38.83, 39.33, 44.20, 48.55, 49.23, 62.74, 64.38, 68.03, 71.70,74.48, 77.20, 81.20, 96.42, 123.11, 126.46, 129.69, 132.39, 132.88,150.21, 170.97, 174.03; IR (KBr) 3496-3395 (br), 2968-2867 (br),1721-1713 (br s), 1376 (s), 1264 (s), 1027 (s), 753 (s) cm⁻¹. Anal.Calcd for C₃₇H₅₆O₉1/2 CHCl₃: C, 63.95; H, 8.08. Found: C, 63.68; H,7.97.

EXAMPLE 15

This example describes the oxidation of FSA-G- 1 to give11-dehydrofusidic acid3-(4,6-di-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside)[FSA-G-3]. To a solution of FSA-G-1 (144 mg, 0.57 mmol) in drydichloromethane (10 mL) was added 12-I-5 triacetoxyperiodinane [the DessMartin reagent; see Dess and Martin, J. Org. Chem. 48:4155 (1983)] (150mg, 0.36 mmol) at room temperature. The reaction mixture was stirred for3.5 hr, whereupon the mixture was diluted with diethyl ether (20 mL).The organic mixture was washed successively with 10% aqueous NaHCO₃ (15mL), 0.1 M aqueous Na₂S₂O₃ (15 mL), and brine (15 mL). The organic layerwas dried over anhydrous magnesium sulfate, and the solvent was removedunder reduced pressure to obtain FSA-G-3 as an anomerically pure, whitepowder (144 mg, 80%): mp 115-116°; TLC R_(f) 0.60 (9/1dichloromethane/methanol); [α]_(D) ²¹+31.2° (c=1.44, CHCl₃); ¹H NMR (360MHz, CDCl₃) δ 0.85 (d, 3H, J=6.3 Hz, 30-CH₃), 1.02 (s, 3H, 19-CH₃), 1.15(s, 3H, 18-CH₃), 1.17 (s, 3H, 32-CH₃), 1.59 (s, 3H, 26-CH₃), 1.67 (s,3H, 27-CH₃), 1.99 (s, 3H, 16-OAc), 2.09 (s, 3H, OAc), 2.10 (s, 3H, OAc),3.63 (br s, 1H, 3-H), 4.15-4.23 (m, 3H, 5′-, 6′-, 6″-H), 5.04 (br s, 1H,1′-H), 5.08 (br s 1H, 24-H), 5.26 (d, 1H, J=9.3 Hz, 4′-H), 5.84 (br s,2H, 2′-H and 3′-H), 5.95 (d, 1H, J=8.6 Hz, 16-H); ¹³C-NMR of the (90.6MHz, CDCl₃) δ 15.94, 17.06, 17.69, 20.21, 20.48, 20.78, 20.99, 21.29,22.89, 25.63, 27.98, 28.67, 28.82, 29.01, 32.38, 34.98, 37.42, 38.08,39.01, 41.08, 44.78, 47.67, 48.66, 58.53, 63.22, 65.47, 66.95, 74.23,81.56, 96.62, 122.50, 128.20, 130.52, 133.85, 148.77, 170.36 (2×C),170.90, 174.12, 210.19; IR (KBr) 3540-3360 (br w), 2954 (br s), 2876(s), 1744 (s), 1373 (w), 1236 (s), 1103 (w), 1037 (s) cm⁻¹.

EXAMPLE 16

This example describes the hydrolysis of FSA-G-3 to give11-dehydrofusidic acid 3-(2,3-dideoxy-α-D-erythro-hex-2-enopyranoside)[FSA-G-4]. To a solution of FSA-G-3 (80 mg, 0.11 mmol) in methanol (10mL) was added 0.1 M aqueous Ba(OH)₂ (4 mL) at room temperature. Themixture was stirred for 3 hr, whereupon the solution was extracted with4/1 chloroform/1-butanol (3×15 mL). The combined organic layers weredried over anhydrous magnesium sulfate and concentrated under reducedpressure. The crude residue thus obtained was purified by silica gelflash chromatography using a chloroform to ethyl acetate gradient as theeluent, providing FSA-G-4 (10:1 α/β-anomers) as a white powder (39 mg,55%): mp 106°; TLC R_(f) 0.22 (9/1 dichloromethane/methanol); [α]_(D)²¹+13° (c=0.57, CHCl₃); ¹H NMR (360 MHz, CDCl₃) δ 0.85 (d, 3H, J=6.5 Hz,30-CH₃), 1.00 (s, 3H, 19-CH₃), 1.12 (s, 3H, 18-CH₃), 1.17 (s, 3H,32-CH₃), 1.59 (s, 3H, 26-CH₃), 1.66 (s, 3H, 27-CH₃), 2.00 (s, 3H,16-OAc), 3.60 (s, 1H, 3-H), 3.75-3.92 (m, 3H, 5′-, 6′-, 6″-H), 4.24 (d,1H, J=8.9 Hz, 4′-H), 4.98 (s, 1H, 1′-H), 5.08 (t, 1H, J=7.1 Hz, 24-H),5.73 (br d, 1H, J=10.1 Hz, 3′-H), 5.90 (d, 1H, J=8.1 Hz, 16-H), and 5.93(d, 1H, J=10.1 Hz, 2′-H)); ¹³C-NMR (90.6 MHz, CDCl₃)δ 15.92, 17.05,17.72, 20.32, 20.54, 21.55, 22.51, 25.65, 28.04, 28.75, 28.99, 31.96,35.28, 37.29, 38.08, 38.66, 41.34, 44.92, 47.96, 48.66, 58.54, 62.70,64.42, 71.19, 74.30, 81.11, 96.45, 122.59, 126.63, 130.65, 132.50,132.96, 147.61, 170.63, 173.38, 210.63; IR (KBr) 3459-3423 (br s),2967-2877 (br s), 1714 (s), 1702 (s), 1036 (s), 753 (s) cm⁻¹.

EXAMPLE 17

This example describes the catalytic hydrogenation of FSA-G-1 to give24,25-dihydrofusidic acid3-(4,6-di-O-acetyl-2,3-dideoxy-α-D-erythro-hexanopyranoside) [FSA-G-5].To a solution of FSA-G-1 (210 mg, 0.29 mmol) in absolute ethanol (10 mL)and dry benzene (30 mL) was added platinum oxide (2 spatula tips, 5 mol%) at room temperature. The air was removed by applying vacuum andflushing the mixture with nitrogen; this procedure was repeated threetimes. The flask was charged with hydrogen gas and the mixture wasstirred for 2 hr, whereupon the hydrogen atmosphere was replaced withnitrogen. The platinum catalyst was removed by filtration, and thereaction mixture was concentrated under reduced pressure, providingFSA-G-5 (10:1 (α/β-anomers) as a white solid (202 mg, 95%): mp 89-90°;TLC F_(f) 0.60 (9/1 dichloromethane/methanol); [α]_(D) ²¹+20.30°(c=0.69, CHCl₃); ¹H NMR (360 MHz, CDCl₃) δ 0.85 (d, 3H, J=6.2 Hz,30-CH₃), 0.87 (d, 6H, J 6.6 Hz, 26-CH₃ and 27-CH₃), 0.92 (s, 3H,19-CH₃), 0.98 (s, 3H, 18-CH₃), 1.38 (s, 3H, 32-CH₃), 1.97 (s, 3H,16-OAc), 2.06 (s, 3H, OAc), 2.08 (s, 3H, OAc), 3.06 (d, 1H, J=11.5 Hz,13-H), 3.57 (br s, 1H, 3-H), 4.06-4.23 (m, 3H, 5′-, 6′-, 6″-H), 4.36 (brs, 1H, 11-H), 4.70 (td, 1H, J=10.0, 4.4 Hz, 4′-H), 4.85 (s, 1H, 1′-H),5.89 (d, 1H, J=8.3 Hz, 16-H); ¹³C-NMR (90.6 MHz, CDCl₃)δ 16.18, 18.13,20.63, 20.81, 20.96, 21.70, 21. 26, 22.70, 24.38, 27.79, 27.93, 28.77,28.95, 29.40, 31.51, 32.96, 35.58, 36.33, 37.08, 37.28, 38.81, 39.08,39.54, 44.07, 45.88, 48.87, 49.16, 63.74, 68.38, 68.49, 69.29, 74.45,81.10, 98.97, 100.09, 131.09, 148.99, 170.32, 170.85, 171.14, 174.62; IR(KBr) 3578-3320 (br s), 2960-2944 (br s), 1738 (s), 1459 (s), 1251 (s),1120 (s), 735 (w) cm⁻.

EXAMPLE 18

This example describes the hydrolysis of FSA-G-5 to give24,25-dihydrofusidic acid 37(2,3-dideoxy-α-D-erythro-hexanopyranoside)[FSA-G-6]. To a solution of FSA-G-5 (30 mg, 0.04 mmol) in methanol (3mL) was added 0.1 M aqueous Ba(OH)₂ (3 mL) at room temperature. Themixture was stirred for 3 hr, whereupon the hydrolyzed product wasextracted with 4/1 chloroform/1-butanol (3×5 mL). The combined organiclayers were dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The crude solid was purified by silica gel flashchromatography using chloroform to ethyl acetate gradient as the eluent,providing an α/β (10:1) anomeric mixture of FSA-G-6 as a white powder(14 mg, 50%): mp 73-74°; TLC R_(f) 0.20 (9/1 dichloromethane/methanol);[α]_(D) ²¹+27.1° (c=0.67, CHCl₃); ¹H NMR (360 MHz, CDCl₃) δ 0.85 (d, 3H,J=5.7 Hz, 30-CH₃), 0.87 (d, 6H, J=6.6 HZ 26-CH₃ and 27-CH₃), 0.91 (s,3H, 18-CH₃), 0.97 (s, 3H, 19-CH₃), 1.37 (s, 3H, 32-CH₃), 1.97 (s, 3H,16-OAc), 3.03 (br d, 1H, J=12.7 Hz, 13-H), 3.53 (br s, 1H, 3-H),3.74-3.84 (m, 3H, 5′-, 6′-, 6″-H), 4.34 (br s, 1H, 11-H), 4.79 (d, 1H,J=2.8 HZ, 1′-1H), 5.87 (d, 1H, J=8.2 Hz, 16-H; ¹³C-NMR (90.6 MHz,CDCl₃)δ 16.04, 17.87, 20.68, 22.60 (2×C), 23.11, 27.84, 28.56, 28.91,29.70, 29.94, 31.05, 32.21, 35.60, 36.60, 36.72 (2×C), 38.71, 38.98,39.49, 44.15, 48.72, 49.23, 63.71, 68.21, 73.63, 74.42, 80.73, 83.73,98.30, 131.10, 149.01, 170.94, 174.71; IR (KBr) 3472-3402 (br s),2953-2932 (br s), 1717 (s), 1376 (s), 1261 (s), 1034 (s), 743 (w) cm⁻¹.

EXAMPLE 19

This example describes the oxidation of FSA-G-5 to give11-dehydro-24,25-dihydrofusidic acid3-(4,6-di-O-acetyl-2,3-dideoxy-α-D-erythro-hexanopyranoside) [FSA-G-7].To a solution of FSA-G-5 (150 mg, 0.2 mmol) in dry dichloromethane (10mL) was added the Dess Martin reagent (152 mg, 0.36 mmol) at roomtemperature under nitrogen atmosphere. The reaction mixture was stirredfor 3.5 hr, whereupon the mixture was diluted with diethyl ether (20mL). The organic mixture was washed successively with 10% aqueous NaHCO₃(15 mL), 0.1 M aqueous Na₂S₂O₃ (15 mL), and brine (15 mL). The organiclayer was dried over anhydrous magnesium sulfate and the solvent wasremoved under reduced pressure to obtain a 7:2 α/βanomeric mixture ofFSA-G-7 as a white solid (140 mg, 95%): mp 95-97°; TLC R_(f) 0.60 (9/1dichloromethane/methanol); [α]_(D) ²¹+46.5° (c=3.0, CHCl₃); ¹H NMR ofthe α anomer (360 MHz, CDCl₃)δ 0.85 (d, 3H, J=6.1 Hz, 30-CH₃), 0.86 (d,6H, J=6.6 HZ, 26-, 27-CH₃), 1.99 (s, 3H, 16-OAc), 2.06 (s, 3H, OAc),2.08 (s, 3H, OAc), 3.57 (br s, 1H 3-H), 3.89 (d, 1H, J=10.0 Hz),4.04-4.22 (m,3H, 5′-, 6′-, 6″-H), 4.69-4.73 (m, 1H, 4′-H), 4.84 (s, 1H,1′H), 5.92 (d, 1H, J=8.3 Hz, 16-H); ¹³C-NMR of the (90.6 MHz CDCl₃)δ16.15, 17.10, 20.47, 20.78, 21.09, 22.51 (2×C), 23.09, 24.27, 27.42,27.80, 28.64, 29.13, 29.29, 30.71, 32.85, 34.88, 37.58, 38.14, 38.48,38.94, 39.28, 41.04, 44.77, 47.32, 48.76, 58.64, 63.37, 68.16, 69.31,74.23, 81.27, 98.90, 131.17, 147.50, 170.15, 170.30, 170.94, 174.39,210.28; IR (KBr) 2958 (s), 2254 (s), 1735 (s), 1689 (s), 1375 (s), 1252(s), 1037 (s), 903 (s), 735 (s) cm⁻¹.

EXAMPLE 20

This example describes the hydrolysis of FSA-G-7 to give11-dehydro-24,25-dihydrofusidic acid3-(2,3-dideoxy-α-D-erythro-hexanopyranoside) [FSA-G-8]. To a solution ofFSA-G-7 (122 mg, 0.17 mmol) in methanol (4 mL) was added 0.1 M aqueousBa(OH)₂ (6 mL) at room temperature. The mixture was stirred for 3 hr,whereupon the hydrolyzed product was extracted with 4/1chloroform/1-butanol (3×5 mL). The combined organic layers were driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The crude solid was purified by silica gel flashchromatography using chloroform to ethyl acetate gradient as the eluent,providing FSA-G-8 (>10:1 α/β anomers) as a white solid (60 mg, 55%): mp71-73°; TLC R_(f) 0.20 (9/1 dichloromethane/methanol); [α]_(D) ²¹+53.70°(c=1.8, CHCl₃); ¹H NMR (360 MHz, CDCl₃) δ 0.85 (d, 3H, J=6.2 Hz,30-CH₃), 0.86 (d, 6H, J=6.6 Hz, 26-, 27-CH₃), 1.02 (s, 3H), 1.17 (s,6H), 2.00 (s, 3H, 16-OAc), 2.91 (br d, 1H, J=12.3 Hz, 13-H), 3.54 (br s,1H, 3-H), 3.60-3.70 (m, 1H), 3.73-3.86 (m, 3H, 5′-, 6′-, 6″-H), 4.80 (s,1H, 1′H), 5.91 (d, 1H, J=8.0 Hz, 16-H; ¹³C-NMR (90.6 MHz, CDCl₃)δ 16.16,17.08, 20.26, 20.60, 21.38, 22.55 (2×C), 22.76, 27.47, 27.82, 28.74,28.91, 29.07, 29.85, 32.38, 35.20, 37.42, 38.16, 38.54, 38.89, 41.27,44.85, 47.60, 48.76, 58.64, 63.48, 67.96, 73.24, 74.21, 77.20, 80.93,98.60, 131.32, 146.72, 170.48, 173.30, 210.56; IR (KBr) 3572 (br), 2927(s), 1717 (s), 1596 (s), 1418 (s), 1121 (s), 616 (s) cm⁻¹.

EXAMPLE 21

This example describes the synthesis of fusidic acid3-[4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-6-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside][FSA-M-1]. To a solution of fusidic acid (500 mg, 1.07 mmol) andhexa-O-acetyl-maltal (720 mg, 1.29 mmol) in dry tetrahydrofuran (35 mL)was added iodine (80 mg, 20 mol %) at room temperature under a nitrogenatmosphere. The mixture was stirred for 12 hr, whereupon the reactionmixture was diluted with chloroform (60 mL). The resulting mixture waswashed with 0.1 M aqueous Na₂S₂O₃ (35 mL) and 10% aqueous NaHCO₃ (35mL). The organic layer was dried over anhydrous magnesium sulfate andthe solvent was removed under reduced pressure. The resulting oilyresidue was purified by silica gel flash chromatography usingdichloromethane/ethyl acetate (1/0 to 0/1, v/v) as the eluent, providingFSA-M-1 (>100:1 α/β-anomers) as a light yellow powder (760 mg, 70%): mp105-108°; TLC R_(f) 0.55 (9/1 dichloromethane/methanol); [c]_(D)²¹+32.10 (c=3.0, CHCl₃); ¹H NMR (360 MHz, CDCl₃)δ 0.87 (d, 3H, J=6.4 Hz,30-CH₃), 0.91 (s, 3H, 19-CH₃), 0.98 (s, 3H, 18-CH₃), 1.38 (s, 3H,32-CH₃), 1.60 (s, 3H, 26-CH₃), 1.67 (s, 3H, 27-CH₃), 1.96 (s, 3H,16-OAc), 2.01 (s, 3H, OAc), 2.03 (s, 3H, OAc), 2.09 (s, 3H, OAc), 2.10(s, 3H, OAc), 2.11 (s, 31H, OAc), 3.08 (d, 3H, J=11.7 Hz, 13-H), 3.62(br s, 1H, 3-H), 4.00-4.14 (m,3H), 4.24-4.35 (m, 4H), 4.83 (dd, 1H,J=10.3, 3.8 Hz), 5.00 (s, 1H, 1′H), 5.03-5.13 (m, 2H), 5.35 (d, 1H,J=3.8 Hz), 5.44 (t, 1H, J=9.9 Hz), 5.80 (m, 3H); ¹³C NMR (90.6 MHz,CDCl₃)δ 15.63, 17.57, 17.73, 20.40 (2×C), 20.48 (3×C), 20.65, 22.77,23.92, 25.51, 28.26, 28.52, 28.79, 30.78, 32.14, 35.52, 36.34, 36.55,36.60, 38.76, 39.19, 44.19, 48.50, 49.04, 61.61, 63.49, 66.89, 67.75(2×C), 68.08, 69.66, 70.06, 70.76, 74.26, 77.18, 80.87, 93.21,96.16,122.93, 127.21, 128.84, 129.34, 132.31, 150.95, 169.41, 169.88,170.36 (2×C), 170.47, 170.56, 174.72; IR (KBr) 3539-3499 (br s),2938-2877 (br s), 1755 (s), 1749 (s), 1741 (s), 1735 (s), 1441 (s), 1373(s), 1255 (s), 1225 (s), 1106 (s), 1039 (s), 754 (s) cm⁻¹.

EXAMPLE 22

This example describes the synthesis of fusidic acid3-[4-O-(2,3,4,6-tetra-O-acetyl- β-D-galactopyranosyl)-6-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside] [FSA-L-1]. To a solution offusidic acid (250 mg, 0.48 mmol) and hexa-O-acetyl-lactal (315 mg, 0.56mmol) in dry tetrahydrofuran (20 mL) was added iodine (40 mg, 20 mol %)at room temperature under nitrogen atmosphere. The mixture was stirredfor 24 hr, whereupon the reaction mixture was diluted with chloroform(30 mL). The resulting mixture was washed with 0.1 M aqueous Na₂S₂O₃ (20mL) and 10% aqueous NaHCO₃ (20 mL). The organic layer was dried overanhydrous magnesium sulfate and the solvent was removed under reducedpressure. The resulting oily residue was purified by silica gel flashchromatography using dichloromethane/ethyl acetate (1/0 to 0/1, v/v) asthe eluent, providing FSA-L-1 (>100:1 α/β-anomers) as a light yellowpowder (317 mg, 65%): mp 73-74°; TLC F_(f) 0.55 (9/1dichloromethane/methanol); [α]D²¹+1.50 (c=1.0,CHCl₃); ¹H NMR (360 MHz,CDCl₃) δ 0.85 (d, 3H, J=6.6 Hz, 30-CH₃), 0.91 (s, 3H, 19-CH₃), 0.96 (s,3H, 18-CH₃), 1.35 (s, 3H, 32-CH₃), 1.59 (s,3H, 26-CH₃), 1.67 (s, 3H,27-CH₃), 1.96 (s, 3H, 16-OAc), 1.98 (s, 3H, OAs), 2.05 (s, 3H, OAc),2.09 (s, 3H, OAc), 2.16 (s, 3H, OAc), 3.06 (d, 3H, J=11.4 Hz, 13-H),3.62 (br s, 1H, 3-H), 3.95 (t, 1H, J=6.8 Hz), 4.04-4.28. (m, 6H), 4.31(br s, 1H, 11-H), 4.60 (d, 1H, J=7.9 Hz), 5.00 (s, 1H, 1′H), 5.03 (d,1H, J=3.3 Hz), 5.10 (t, 1H, J=6.9 Hz), 5.22 (dd, 1H, J=10.4, 7.9 Hz),5.38 (d, 1H, J=3.1 Hz), 5.79 (dt, 1H, J=10.4, 2.2 Hz, 3′-H), 5.89 (d,1H, J=8.3 Hz, 16-H), 6.06 (d, 1H, J=10.4 Hz, 2′-H); ¹³C NMR (90.6 MHz,CDCl₃)δ 15.77, 17.71, 17.89, 20.60 (5×C), 20.80, 22.79, 24.12, 25.65,28.33, 28.67, 28.93, 31.01, 32.37, 35.64, 36.40, 36.75, 38.89, 39.32,44.25, 48.65, 49.10, 61.20, 63.36, 66.79, 67.20, 67.99, 68.82, 70.53,70.81 (2×C), 73.81, 74.40, 77.20, 80.76, 96.45, 102.11, 122.99, 127.72,129.48, 130.27, 131.42, 132.53, 151.08, 169.44, 170.08, 170.22, 170.45(2×C), 170.78, 174.39; IR (KBr) 2955 (br), 1752 (s), 1371 (s), 1229 (s),1040 (s), 754 (s) cm⁻¹.

EXAMPLE 23

This example describes the synthesis of fusidic acid3-(4,6-bis-O-(chloroacetyl)-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside)[FSA—ClAc-G-1]. To a solution of 345 mg of fusidic acid (0.66 mmol) and300 mg of tri-O-(chloroacetyl)-glucal (0.80 nmmol, 1.2 equiv) in 20 mLof dry THF was added 45 mg of iodine (0.17 mmol, 26 mol%) at roomtemperature under nitrogen atmosphere. The mixture was stirred for 4days, whereupon the reaction mixture was diluted with 45 mL of diethylether. The resulting mixture was washed first with 30 mL of 0.1 Maqueous Na₂S₂O₃ and then with 30 mL of 10% aqueous NaHCO₃. The organiclayer was dried over anhydrous sodium sulfate and the solvent wasremoved by rotary evaporation. The resulting oily residue was purifiedby silica gel flash column chromatography using a gradient elution withchloroformn/ethyl acetate (1/0 to 0/1, v/v), providing FSA—ClAc-G-1(20:1 α/β-anomers) as an off-white solid (200 mg, 38%): mp 88-89° C.;TLC R_(f) 0.48 (9:1 dichloromethane/ methanol); [α]D²²−2.5°(c=0.60,CHCl₃); ¹H NMR (360 MHz, CDCl₃)δ 0.87 (d,3H, J=6.6 Hz, 30-CH₃),0.91 (s, 3H, 19-CH₃), 0.97 (s,3H, 18-CH₃), 1.35 (s, 3H, 32-CH₃, 1.60 (s,3H 26-CH₃), 1.68 (s, 3H, 27-CH₃), 1.96 (s, 3H, 16-OAc), 3.04 (br d, 1H,J=9.0 Hz, 13-H), 3.60-3.66 (m or apparent diffused ddd, 1H, 3-H),4.03-4.33 (m, 3H, 5′-, 6′-, 6″-H), 4.12 (s, 4H, 2×CH ₂Cl), 4.35 (br s,1H, 11-H 0, 5.05 (s, 1H, 1′-H), 5.10 (t, 1H, J=7.2 Hz, 24-H), 5.35 (dd,1H, J=9.6, 1.2 Hz, 4+H), 5.84 (br d, 1H, J=11.1 Hz, 3′-H), 5.89 (br d,1H, J=11.1 Hz, 2′-H), 5.90 (br d, 1H, J=9.3 Hz, 16-H); ¹³C NMR (90.6MHz, CDCl₃) δ 15.80, 17.71 17.92, 20.53, 22.79, 24.07, 25.66, 28.3428.63, 28.96, 31.08, 32.36, 35.62, 36.31, 36.77, 36.86, 38.88, 39.30,40.68 (2×C), 44.26, 48.63, 49.08, 64.71, 66.41, 67.26, 68.19, 77.02,81.48, 96.49, 122.92, 127.13, 128.97, 129.51, 132.59, 151.21, 166.88,167.17, 170.49, 174.99; IR (KBr) 3604-3310 (br), 2955 (br), 2875 (br),1763 (s), 1739 (s), 1688 (s), 1445 (w), 1376 (s), 1253 (s), 1216 (w),1167 (s), 1027 (s), 763 (m), 752 (m) cm⁻¹.

EXAMPLE 24

This example describes the hydrolysis of FSA-ClAc-G-1 to give FSA-G-2. Asolution of FSA—ClAc-G-1 (110 mg, 0.14 mmol) in 2 mL of THF was dilutedwith a mixture of 3 mL of methanol and 1 mL of water. The solution wastreated with 42 mg of KHCO₃ in 1 mL of water at room temperature and theresulting mixture was stirred for 3 hrs, whereupon the reaction mixturewas extracted with chloroform (2×15 mL). The combined organic layerswere dried over anhydrous magnesium sulfate and the solvent removedunder reduced pressure. The resulting crude products were purified bysilica gel flash column chromatography by following the same procedureas described for the preparation of FSA-G-2 at Example 14, providing 46mg of FSA-G-2 (45%).

EXAMPLE 25

This example describes the glycosylation of fusidic acid with eitherhexa-O-(chloroacetyl)-maltal to give fusidic acid3-[4-O-(2,3,4,6-tetra-O-(chloroacetyl)-α-D-glucopyranosyl)-6-O-(chloroacetyl)-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside] [FSA-ClAc-M-1] orhexa-O-(chloroacetyl)-lactal to give fusidic acid3-[4-O-(2,3,4,6-tetra-O-(chloroacetyl)-α-D-galactopyranosyl)-6-O-(chloroacetyl)-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside][FSA-ClAc-L-1]. Fusidic acid will be dissolved in an appropriate amountof CH₂Cl₂ (˜50 mL/gram) and 1.1 equivalents ofhexa-O-(chloroacetyl)-maltal or hexa-O-(chloroacetyl)-lactal and 0.2molar equivalents of a catalyst will be added.

If I₂ is chosen as the catalyst, then the reaction will be run at roomtemperature for at least one day. If no reaction is observed, then thereaction mixture will be heated to reflux. Other solvents, such as THFor acetone, could also be tried if the reaction proceeds slowly. Oncethe reaction is complete or reaches an apparent state of equilibrium, itwill be worked up by standard procedures: dilution in an appropriatesolvent (such as CH₂Cl₂ or ether); successive washings with 0.1 Maqueous Na₂S₂O₃, water, and brine; drying over anhydrous sodium sulfate;filtering; and removal of the solvent under reduced pressure. Silica gelchromatography using an appropriate solvent system (such as ethylacetate/hexanes) will provide an acceptable yield of purified product.

If BF₃ etherate is chosen as a catalyst for the glycosylation reaction,the reaction mixture will first be cooled to −23° and then allowed towarm slowly to room temperature if needed. The reaction will proceedreadily at room temperature or less. Once the reaction is complete orreaches an apparent state of equilibrium, it would be worked up by thestandard procedures, and the product purified as outlined above.

EXAMPLE 26

This example describes the hydrolysis of FSA-ClAc-M-1 to give fusidicacid3-[4-O-(α-D-glucopyranosyl)-2,3-dideoxy-α-D-eythro-hex-2-enopyranoside][FSA-M-2] or the hydrolysis of FSA-ClAc-L-1 to give fusidic acid 3-[4-O-(β−7D-galactopyranosyl)-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside][FSA-L-2]. After dissolving either of the two glycosides in methanolwith a small amount of water, approximately 10 equivalents of KHCO₃ willbe added and stirred at room temperature. After hydrolysis of thechloroacetate groups, the reaction mixture will be neutralized by usingan ion exchange resin, although this step may not be necessary due tothe acidic nature of the silica gel to be used in the purification.Subsequently, the solvent will be removed under reduced pressure, andsilica gel purification with an appropriate solvent system (methanol ineither ethyl acetate or a halogenated solvent such as chloroform ordichloromethane) should provide either FSA-M-2 or FSA-L-2 depending onthe starting material employed.

EXAMPLE 27

This example describes the glycosylation of fusidic acid with theactivated form of a glycal, i.e.,di-O-acetyl-O-((o-methoxy)benzoyl)-glucal,penta-O-acetyl-O-((o-methoxy)benzoyl)-maltal, orpenta-O-acetyl-O-((o-methoxy)benzoyl)-lactal. Fusidic acid will bedissolved in an appropriate solvent such as CH₂Cl₂ or. THF and 1.1equivalents of either di-O-acetyl-O-((o-methoxy)benzoyl)-glucal,penta-O-acetyl-O-((o-methoxy)benzoyl)-maltal, orpenta-O-acetyl-O-((o-methoxy)benzoyl)-lactal and 0.2 molar equivalentsof a catalyst such as I₂ will be added. The reaction will then bestirred at room temperature and monitored by TLC; the reaction willprobably require much less time than their inactivated glycalcounterparts. However, if necessary, the reaction mixture will berefluxed. Once the reaction is complete or has reached an apparent stateof equilibrium, it will be worked up by standard procedures: dilution inan appropriate solvent (such as CH₂Cl₂ or ether); successive washingswith 0.1 M aqueous Na2S₂O₃, water, and brine; drying over anhydroussodium sulfate; filtering; and removal of the solvent under reducedpressure should provide the crude product. Silica gel chromatographyusing a chloroform to ethyl acetate gradient should provide FSA-G-1,FSA-M-1, and FSA-L-1, respectively, depending on the activated glycalchosen.

EXAMPLE 28

This example describes the preparation of glycosylated analogs offusidic acid that have a carbohydrate unit at C-24 of the aglycon.First, the hydroxyl groups at C-3 and C-11 and the carboxylic acid atC-21 will be protected. Fusidic acid will be dissolved in dry THFcontaining 3 equivalents of pyridine under a nitrogen atmosphere and thesolution will be cooled to 0° C., whereupon 2.5 equivalents ofmonochloroacetyl chloride in THF will be added dropwise. The reactionmixture will be warmed to room temperature and will be stirred until thereaction is complete as indicated by TLC. The reaction mixture will beworked up using standard protocols. The crude reaction product may beused in the next step, or it may first need to be purified by silica gelchromatography. In either case, the material will be dissolved in drydichloromethane under a nitrogen atmosphere and the resulting solutionwill be treated with 1.1 equivalents of a diazomethane precursor such asDiazold or N,N′-dimethyl-N, N′-dinitrosoterephthalamide which upontreatment with KOH produces diazomethane. The reaction will be stirredat room temperature until the TLC indicates that the reaction iscomplete. Workup following standard protocols and silica gelchromatography will give the molecule depicted in FIG. 17.

Second, the hydroxyl group will be introduced at C-24 by a hydroborationreaction. The molecule in FIG. 17 will be dissolved in dry THF under anitrogen atmosphere and one equivalent of either (+)-Alpine borane or(−)-Alpine borane will be added. Alternatively, an achiral hydroborationreagent such as 9-borabicyclo[3.3.1]nonane [9-BBN] can be employed. Thereaction will be achieved by heating if necessary. Oxidation of theresulting borane followed by standard workup procedures and silica gelchromatography will give the molecule in FIG. 18 having a hydroxyl groupat C-24. Oxidation can be effected by either reacting the molecule withone equivalent of sodium hydroxide and an excess of 30% aqueous hydrogenperoxide while maintaining the reaction mixture at room temperature, ortreating the borane with two equivalents of oxygen followed by 30%aqueous hydrogen peroxide. [For examples of the hydroboration andoxidation reactions, see Brown, “Organic Synthesis via Boranes” 61-62,107-08, 110-12 (1975).] The particular C-24 epimer to be obtained(either R or S) will depend on the chirality of the Alpine boranereagent used.

The molecule in FIG. 18 will be glycosylated by following the standardprocedure described in Examples 23 and 25 which employs thepermonochloroacetylated glycals. Thus, a number of glycosylated fusidicacid derivatives such as that depicted in FIG. 20 will be prepared wherethe carbohydrate attached at the C-24 hydroxyl will be, for example, thepermonochloroacetylated glucal, maltal, or lactal. The protecting groupsof the glycosylated derivative can be hydrolyzed by following theprocedure outlined in Experimentals 24 and 14 to hydrolyze themonochloroacetyls and methyl ester, respectively. These reactions willgive the molecule shown in FIG. 21.

Alternatively, the modified fusidic acid of FIG. 18 can first bedeprotected by following the protocol in Experimental 24 to give themodified fusidic acid in FIG. 19 which has no protected hydroxyl groupsyet still has a protected carboxylic acid at C-21. Reaction of thiscompound with 2.1 equivalents of a permonochloroacetylated glycalaccording to the protocol in Experimentals 23 and 25 will give the twiceglycosylated analog of fusidic acid as shown in FIG. 22. The protectinggroups can then be removed as discussed above by following Experimentals24 and 14 to give the molecule depicted in FIG. 23.

EXAMPLE 29

This example describes the preparation of glycosylated analogs offusidic acid that have a carbohydrate unit at C-25 of the aglycon. As inExample 27, the hydroxyl groups at C-3 and C-11 and the carboxylic acidat C-21 will be protected to give the molecule depicted in FIG. 17.

Second, the hydroxyl group will be introduced at C-25 by anoxymercuration-demercuration process. The molecule in FIG. 17 will bedissolved in aqueous THF and one equivalent of Hg(ClO₄)₂ will be added.If necessary, the reaction mixture will be warmed. Addition of 1.1equivalents of NaBH₄ followed by standard workup and purificationprocedures will give the molecule depicted in FIG. 24.

The molecule in FIG. 24 will be glycosylated by following the standardprocedure described in Examples 23 and 25 which employs thepermonochloroacetylated glycals. Thus, a number of glycosylated fusidicacid derivatives such as that depicted in FIG. 26 will be prepared wherethe carbohydrate attached at the C-25 hydroxyl will be, for example, thepermonochloroacetylated glucal, maltal, or lactal. The protecting groupsof the glycosylated derivative can be hydrolyzed by following theprocedure outlined in Experimentals 24 and 14 to hydrolyze themonochloroacetyls and methyl ester, respectively. These reactions willgive the molecule shown in FIG. 27.

Alternatively, the modified fusidic acid of FIG. 24 can first bedeprotected by following the protocol in Experimental 24 to give themodified fusidic acid in FIG. 25 which has no protected hydroxyl groupsyet still has a protected carboxylic acid at C-21. Reaction of thiscompound with 2.1 equivalents of a permonochloroacetylated glycalaccording to the protocol in Experimentals 23 and 25 will give the twiceglycosylated analog of fusidic acid as shown in FIG. 28. The protectinggroups can then be removed as discussed above by following Experimentals24 and 14 to give the molecule depicted in FIG. 29.

What is claimed is:
 1. A glycosylated analog of fusidic acid synthesizedby a method comprising the steps: a) providing in any order: i) anunmodified fusidic acid, wherein said fusidic acid has an acetate groupat the C-16 position, ii) a derivatizing reagent selected from the groupconsisting of carbohydrate glycals and activated carbohydrate glycals,wherein said carbohydrate glycals and said activated carbohydrateglycals are olefins, and iii) a catalyst; b) reacting said hydroxylatedfusidic acid, said derivatizing reagent, and said catalyst underconditions such that a glycosylated analog of fusidic acid is produced;and c) Hydrolyzing said glycosylated analog of fusidic acid underconditions such that said acetate group at said C-16 position is nothydrolyzed.
 2. The glycosylated analog of fusidic acid of claim 1,wherein said hydrogenating step further comprises hydrogenation withaqueous Ba(OH)₂ of aqueous KHCO₃.
 3. The glycosylated analog of fusidicacid of claim 1, further comprising the step of oxidizing saidglycosylated analog of fusidic acid.
 4. The glycosylated analog offusidic acid of claim 3, wherein said oxidizing step further comprisesoxidizing with 12-I-5 triacetoxyperiodinane.
 5. The glycosylated analogof fusidic acid of claim 1, further comprising the step of hydrogenatingsaid glycosylated analog of fusidic acid.
 6. The glycosylated analog offusidic acid of claim 1, wherein said hydrogenating step furthercomprises hydrogenation with platinum oxide.
 7. The glycosylated analogof fusidic acid of claim 1, further comprising the steps of hydrolyzingand oxidizing said glycosylated analog of fusidic acid.
 8. Theglycosylated analog of fusidic acid of claim 1, further comprising thesteps of hydrolyzing, oxidizing, and hydrogenating said glycosylatedanalog of fusidic acid.
 9. The glycosylated analog of fusidic acid ofclaim 1, further comprising the steps of hydrolyzing and hydrogenatingsaid glycosylated analog of fusidic acid.
 10. The glycosylated analog offusidic acid of claim 1, further comprising the steps of oxidizing andhydrogenating said glycosylated analog of fusidic acid.
 11. Theglycosylated analog of fusidic acid of claim 1, wherein said catalysthas a molar percentage of about 20%.
 12. The glycosylated analog offusidic acid of claim 1, wherein said catalyst is selected from thegroup consisting of iodine and BF₃·etherate.
 13. The glycosylated analogof fusidic acid of claim 1, wherein said derivatizing reagent isselected from the group consisting of monosaccharides and disaccharides.14. A glycosylated analog of fusidic acid synthesized by a methodcomprising the steps: a) providing in any order: i) an unmodifiedfusidic acid, wherein said fusidic acid has an acetate group at the C-16position, ii) a derivatizing reagent selected from the group consistingof carbohydrate glycals and activated carbohydrate glycals, wherein saidcarbohydrate glycals and said activated carbohydrate glycals areolefins, iii) one or more protecting groups, iv) a catalyst, v) anhydroboration reagent, and vi) a oxidation reagent; b) reacting saidunmodified fusidic acid and said one or more protecting groups, toprovide a protected fusidic acid; c) reacting said protected fusidicacid with said hydroboration reagent to provide a borane intermediate;d) oxidizing said borane intermediate with said oxidation reagent toprovide a hydroxylated fusidic acid; and e) reacting said hydroxylatedfusidic acid, said derivatizing reagent and said catalyst underconditions such that a glycosylated analog of fusidic acid is produced.15. The glycosylated analog of fusidic acid of claim 14, wherein saidhydroboration reagent is selected from the group consisting of chiralboranes, achiral boranes, (+)-Alpine borane, (−)-Alpine borane, and9-borabicyclo[3.3.1]nonane.
 16. the glycosylated analog of fusidic acidof claim 14, wherein said oxidation reagent comprises aqueous hydrogenperoxide.
 17. The glycosylated analog of fusidic acid of claim 14,wherein said derivatizing reagent is selected from the group consistingof monosaccharides and disaccharides.
 18. The glycosylated analog offusidic acid claim 14, further comprising the step of hydrolyzing saidglycosylated analog of fusidic acid under conditions such that saidacetate group at said C-16 position is not hydrolyzed.
 19. Theglycosylated analog of fusidic acid of claim 18, wherein saidhydrolyzing step further comprises hydrolyzing with aqueous Ba(OH)₂ oraqueous KHCO₃.
 20. The glycosylated analog of fusidic acid of claim 14,wherein said catalyst has a molar percentage of about 20%.
 21. Theglycosylated analog of fusidic acid of claim 14, wherein said catalystis selected from the group consisting of iodine and BF₃. etherate.
 22. Aglycosylated analog of fusidic acid synthesized by a method comprisingthe steps: a) providing in any order: i) an unmodified fusidic acid,wherein said fusidic acid has an acetate group at the C-16 position, ii)a derivatizing reagent selected from the group consisting ofcarbohydrate glycals and activated carbohydrate glycals, wherein saidcarbohydrate glycals and said activated carbohydrate glycals areolefins, iii) one or more protecting groups, iv) a catalyst, v) anoxymercuration reagent, and vi) a demercuration reagent; b) reactingsaid unmodified fusidic acid and said one or more protecting groups, toprovide a protected fusidic acid; c) reacting said protected fusidicacid with said oxymercuration reagent to provide an intermediate; d)reacting said intermediate with said demercuration reagent to provide ahydroxylated fusidic acid; and e) reacting said hydroxylated fusidicacid, said derivatizing reagent and said catalyst under conditions suchthat a glycosylated analog of fusidic acid is produced.
 23. Theglycosylated analog of fisidic acid of claim 22, wherein saidoxyrnercuration reagent is Hg(ClO₄)₂.
 24. The glycosylated analog offusidic acid of claim 22, wherein said demercuration reagent is NaBH₄.25. The glycosylated analog of fusidic acid of claim 22, wherein saidderivatizing reagent is selected from the group consisting ofmonosaccharides and disaccharides.
 26. The glycosylated analog offusidic acid of claim 22, further comprising the step of hydrolyzingsaid glycosylated analog of fusidic acid under conditions such that saidacetate group at said C-16 position is not hydrolyzed.
 27. Theglycosylated analog of fusidic acid of claim 26, wherein saidhydrolyzing step further comprises hydrolyzing with aqueous Ba(OH)₂ oraqueous KHCO₃.
 28. The glycosylated analog of fusidic acid of claim 26,wherein said catalyst has a molar percentage of about 20%.
 29. Theglycosylated analog of fusidic acid of claim 26, wherein said catalystis selected from the group consisting of iodine and BF₃ ∩etherate. 30.The glycosylated analog of fusidic acid of claim 13, wherein saidderivatizing reagent is selected from the group consisting of glucal,lactal, maltal, tri-O-acetyl glucal, hexa-O-acetyl-maltal,hexa-O-acetyl-lactal, tri-O-(chloroacetyl)-glucal,hexa-O-(chloroacetyl)-maltal, hexa-O-(chloroacetyl)-lactal,di-O-acetyl-((o-methoxy)benzoyl)-glucal,penta-O-acetyl-O-((o-methoxy)benzoyl)-maltal, andpenta-O-acetyl-O-((o-methoxy)benzoyl)-lactal.
 31. The glycosylatedanalog of fusidic acid of claim 17, wherein said derivatizing reagent isselected from the group consisting of glucals, lactals, maltals,tri-O-acetyl glucal, tri-O-(chloroacetyl)-glucal,hexa-O-(chloroacetyl)-maltal, and hexa-O-(chloroacetyl)-lactal.
 32. Theglycosylated analog of fusidic acid of claim 25, wherein saidderivatizing reagent is selected from the group consisting of glucals,lactals, maltals, tri-O-acetyl glucal, tri-O-(chloroacetyl)-glucal,hexa-O-(chloroacetyl)-maltal, and hexa-O-(chloroacetyl)-lactal.